U.S. patent number 11,052,230 [Application Number 15/806,054] was granted by the patent office on 2021-07-06 for implantable encapsulation devices.
This patent grant is currently assigned to W. L. Gore & Associates, Inc.. The grantee listed for this patent is W. L. Gore & Associates, Inc.. Invention is credited to Edward H. Cully, Edward Gunzel, Keith Knisley, Greg Rusch, Lauren Zambotti.
United States Patent |
11,052,230 |
Cully , et al. |
July 6, 2021 |
Implantable encapsulation devices
Abstract
The present disclosure relates to implantable encapsulation
devices for housing a biological moiety or a therapeutic device
that contains a biological moiety. Particularly, aspects of the
present disclosure are directed to an implantable apparatus that
includes a distal end, a proximal end, a manifold including at
least one access port positioned either at the distal end or the
proximal end, and a plurality of containment tubes affixed to the
manifold and in fluid communication with the at least one access
port. Additionally, the encapsulation device may contain a flush
port and a tube that are fluidly connected to the manifold. The
containment tubes may contain therein a biological moiety (e.g.,
cells) or a therapeutic device (e.g. a cell encapsulation
member).
Inventors: |
Cully; Edward H. (Flagstaff,
AZ), Gunzel; Edward (Oxford, PA), Knisley; Keith
(Flagstaff, AZ), Rusch; Greg (Newark, DE), Zambotti;
Lauren (Wilmington, DE) |
Applicant: |
Name |
City |
State |
Country |
Type |
W. L. Gore & Associates, Inc. |
Newark |
DE |
US |
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Assignee: |
W. L. Gore & Associates,
Inc. (Newark, DE)
|
Family
ID: |
1000005658639 |
Appl.
No.: |
15/806,054 |
Filed: |
November 7, 2017 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20180126134 A1 |
May 10, 2018 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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62419204 |
Nov 8, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61L
31/148 (20130101); A61L 31/16 (20130101); A61F
2/022 (20130101); A61L 31/14 (20130101); A61M
31/002 (20130101); A61L 31/048 (20130101); A61L
31/146 (20130101); A61M 39/0247 (20130101); A61K
9/0092 (20130101); A61M 2039/0282 (20130101); A61L
2400/16 (20130101); A61F 2002/30235 (20130101); A61M
2039/0264 (20130101); A61M 39/04 (20130101) |
Current International
Class: |
A61M
31/00 (20060101); A61L 31/04 (20060101); A61K
9/00 (20060101); A61F 2/02 (20060101); A61L
31/14 (20060101); A61M 39/04 (20060101); A61L
31/16 (20060101); A61M 39/02 (20060101); A61F
2/30 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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1703175 |
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Nov 2005 |
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CN |
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101022769 |
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Aug 2007 |
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CN |
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0746343 |
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Apr 1995 |
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EP |
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WO 91/00119 |
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Jan 1991 |
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WO |
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WO93/21902 |
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Nov 1993 |
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WO |
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WO98/51236 |
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Nov 1998 |
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WO |
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WO2005/097219 |
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Oct 2005 |
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WO |
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WO2011/025977 |
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Mar 2011 |
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WO |
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Other References
International Search Report PCT/US2017/060494 dated Jun. 6, 2018.
cited by applicant.
|
Primary Examiner: Mehta; Bhisma
Assistant Examiner: Ponton; James D
Attorney, Agent or Firm: Miller; Amy L.
Claims
What is claimed is:
1. An implantable encapsulation device comprising: a plurality of
containment tubes interconnected by connection members, each said
containment tube having a first access port at a first end thereof
and a second access port at a second end thereof, and a removable
manifold fluidly connected to said containment tubes at said first
end, wherein said containment tubes are substantially parallel to
each other along a length of said device, wherein said containment
tubes comprise a porous composite material including: an outer
porous polymeric layer that permits ingrowth of vascular tissue;
and an inner polymeric layer disposed adjacent to said outer porous
polymeric layer, said inner polymeric layer being impervious to
cellular or vascular ingrowth, wherein said connection members are
periodically spaced along a length of said containment tubes a
distance from each other, and wherein said plurality of containment
tubes are fluidly interconnected by said connection members.
2. The device of claim 1, further comprising a flush port and a
tube fluidly connected to said removable manifold.
3. The device of claim 1, wherein said connection members are
connected to said containment tubes at an angle greater than zero
degrees and less than 90 degrees.
4. The device of claim 1, further comprising a woven textile, a
non-woven textile, or a knit.
5. The device of claim 1, further comprising resealable caps
affixed to each of said second access ports to seal said second end
of said containment tubes.
6. The device of claim 1, wherein said containment tubes each
comprise a lumen for reception and containment of a biological
moiety or therapeutic device therein.
7. The device of claim 6, wherein the therapeutic device comprises
a drug delivery device, a gene therapy device, a cell encapsulation
device and combinations thereof.
8. The device of claim 7, wherein said biological moiety is a
plurality of cells.
9. The device of claim 6, wherein the therapeutic device is
removably sealed to said manifold, said manifold being fluidly
connected to said containment tubes at said first end.
10. The device of claim 6, wherein the therapeutic device includes
a grasping structure.
11. The device of claim 1, wherein said containment tubes have
thereon a bio-absorbable material.
12. The device of claim 1, wherein said containment tubes are
stacked upon one another in a z-direction.
13. The device of claim 1, wherein each of the plurality of
containment tubes maintains a consistent cylindrical
cross-section.
14. The device of claim 1, further comprising a bio-absorbable
material in at least one of a solid form and a self-cohered
web.
15. The device of claim 14, wherein the bio-absorbable material is
formed as a solid structure with a tapered leading edge.
16. The device of claim 1, wherein said containment tubes comprise
a shape memory material.
17. A cell encapsulation device comprising: a plurality of
containment tubes substantially parallel to each other along a
length of the containment tubes, each said containment tube having
a first access port at a first end thereof and a second access port
at a second end thereof; resealable caps sealably connected to each
of said first access port of said containment tubes; wherein the
containment tubes are independently movable from each other down
the length of the containment tubes, and wherein said containment
tubes comprise a porous composite material including: an outer
porous polymeric layer that permits ingrowth of vascular tissue;
and an inner polymeric layer disposed adjacent to said outer porous
polymeric layer, said inner polymeric layer being impervious to
cellular or vascular ingrowth.
18. The device of claim 17, comprising a manifold, wherein the
containment tubes are fluidly connected by a flush port connected
to the manifold via a tube.
19. The device of claim 18, wherein said manifold comprises at
least two openings with hinged structures positioned between said
at least two openings.
20. The device of claim 19, wherein each said containment tube is
affixed to one of said openings in said manifold.
21. The device of claim 18, wherein said flush port and said tube
lie in a same plane as said containment tubes.
22. The device of claim 17, wherein each said containment tube
comprises a lumen for reception and containment of a biological
moiety or therapeutic device therein.
23. The device of claim 22, wherein the therapeutic device
comprises a drug delivery device, a gene therapy device, a cell
encapsulation device and combinations thereof.
24. The device of claim 23, wherein said biological moiety is a
plurality of cells.
25. The device of claim 22, wherein said biological moiety is a
plurality of cells.
26. The device of claim 25, wherein the therapeutic device is
removably sealed to a manifold.
27. The device of claim 26, wherein the therapeutic device includes
a grasping structure.
28. The device of claim 17, wherein each of the plurality of
containment tubes maintains a consistent cylindrical
cross-section.
29. The device of claim 17, wherein said containment tubes have
thereon a bio-absorbable material.
30. The device of claim 29, wherein said bio-absorbable material is
in at least one of a solid form and a self-cohered web.
31. The device of claim 29, wherein the bio-absorbable material is
a solid structure with a tapered leading edge.
32. The device of claim 17, wherein said containment tubes comprise
a shape memory material.
33. The device of claim 17, comprising: a manifold fluidly
connected to each of the second access ports at the second ends;
and a flush port fluidly connected to the manifold via a tube.
34. The device of claim 17, wherein the containment tubes are
connected by connection members spaced a distance from each other
down a length of the containment tubes.
35. The device of claim 34, wherein the containment tubes are
independently movable between the connection members.
36. The device of claim 34, wherein the containment tubes are
fluidly interconnected by the connection members.
37. An encapsulation device comprising: a plurality of containment
tubes substantially parallel to each other, each of said
containment tubes having a first access port at a first end thereof
and a second access port at a second end thereof; and a resealable
first manifold fluidly connected to each of said first access
ports, a second manifold fluidly connected to each of said second
access ports; and a flush port fluidly connected to the second
manifold, wherein each of said containment tubes comprises a porous
composite material including: an outer porous polymeric layer that
permits ingrowth of vascular tissue; and an inner polymeric layer
disposed adjacent to the outer porous polymeric layer, said inner
polymeric layer being impervious to cellular or vascular
ingrowth.
38. The device of claim 37, further comprising interconnection
members, wherein a biological moiety is housed within lumens of
each of said containment tubes and within each of said
interconnection members.
39. The device of claim 38, wherein said biological moiety is a
plurality of cells.
40. The device of claim 38, wherein said containment tubes and said
interconnection members have thereon a bio-absorbable material.
41. The device of claim 40, wherein said bio-absorbable material is
in at least one of a solid form and a self-cohered web.
42. The device of claim 40, wherein the bio-absorbable material is
a solid structure with a tapered leading edge.
43. The device of claim 38, wherein each of the plurality of
containment tubes and interconnection members maintain a consistent
cylindrical cross-section.
44. The device of claim 37, wherein at least one containment tube
of said plurality of containment tubes comprises a shape memory
material.
45. The device of claim 37, further comprising a resealable cap to
cover the flush port.
46. A cell encapsulation device comprising: a plurality of
containment tubes, each said containment tube having a first access
port at a first end thereof and a second access port at a second
end thereof; a manifold located at a point a distance between said
first ends and said second ends of said containment tubes, said
manifold being fluidly connected to each of said containment tubes
at said point; a divider element located within said manifold to
form a first portion and second portion of each said containment
tube; and a flush port fluidly connected to said manifold by a
tube, wherein said flush port is sealably connected to said
containment tubes, and wherein said point is centrally located
between said first ends and said second ends.
47. An encapsulation device comprising: a plurality of containment
tubes substantially parallel to each other, each of said
containment tubes having a first access port at a first end thereof
and a second access port at a second end thereof; a first removable
manifold fluidly connected to each of the first access ports; a
second removable manifold fluidly connected to each of the second
access ports; a first flush port fluidly connected to the first
manifold; and a second flush port fluidly connected to the second
manifold, wherein each said containment tube comprises a porous
composite material including: an outer porous polymeric layer that
permits ingrowth of vascular tissue; and an inner polymeric layer
disposed adjacent to said outer porous polymeric layer, said inner
polymeric layer being impervious to cellular or vascular ingrowth.
Description
FIELD
The present invention relates to implantable biological devices,
and more particularly, to implantable encapsulation devices for
housing a biological moiety.
BACKGROUND
Biological therapies are increasingly viable methods for treating
peripheral artery disease, aneurysm, heart disease, Alzheimer's and
Parkinson's diseases, autism, blindness, diabetes, and other
pathologies.
With respect to biological therapies in general, cells, viruses,
viral vectors, bacteria, proteins, antibodies, and other biological
moieties may be introduced into a patient by surgical and/or
interventional methods that place the biological moiety into a
tissue bed of a patient. Surgical techniques include blunt planar
dissection into a tissue or organ. Interventional techniques
include injection to a target site via catheter or needle. These
methods cause trauma to host tissue, leading to inflammation, lack
of vascularity, and immune reactions, all of which can reduce
viability and efficacy of the biological moiety. Interventional
methods may also reduce the viability and efficacy of the
biological moiety due to shearing forces experienced during
transport through a fine-bore needle or catheter. Additionally,
increases in pressure caused by the injection of the biological
moiety into dense tissue can induce trauma to the biological
moiety. As a result, implanted moieties often do not engraft and
may undesirably migrate from the injection site.
In some instances, the biological moiety is protected from the host
immune system prior to introduction into a body. One way of
protecting the biological moiety is to encapsulate the moiety prior
to introducing the biological moiety into tissue of a patient.
While the device restricts access to elements of the host's immune
system, it must also allow for the passage of nutrients and other
biomolecules into the device to keep the biological moiety viable
throughout its life (e.g., loading, implantation, and explanation).
However, there remains many challenges with the effectiveness of
current encapsulation systems through various stages of its life
cycle. One challenge includes maintaining survival of the
biological moiety during the implantation and healing phase where
the biological moiety is exposed to a hypoxic environment with a
limited source of oxygen and nutrients. There are also challenges
of scalability of designing the encapsulation device for various
therapies and dose ranges. One example is the need to scale various
device geometries through pre-clinical animal models to a
therapeutic dose in humans without changing critical design
dimensions that would result in a different environment for the
biological moiety. Additionally as the biological moiety reaches
the end of life, there is a desire to extend the useful life of the
encapsulation device or preserve the surface area in the region of
the implant such that the area can be re-used for future
therapies.
Therefore, there remains a need for devices that encapsulate cells
and other biological moieties that are scalable to different sizes,
are able to incorporate various types of biological moieties and/or
sizes of biological moieties, and can be easily accessed to remove
and/or replace a therapeutic device to allow for leveraging
different therapies at different stages of the device life or for
extending the useful life of the device through replacement.
SUMMARY
One aspect relates to an implantable encapsulation device that
includes a single containment tube, a first access port located at
the first end of the containment tube, a second access port located
at the second end of the containment tube, a flush port fluidly
connected to the second access port via a tube, and a cap
releasably attached to the first end of the containment tube and
covering the first access port. The flush port may also include a
resealable cap. The containment tube may contain therein a
biological moiety (e.g., cells) or a therapeutic device (e.g. a
cell encapsulation member).
A second aspect relates to an implantable encapsulation device that
includes a containment tube that has a first end and a second end
and a single access port at one end (e.g., the first end). The
other end (e.g., the second end) may simply be the end of the
containment tube or a permanent seal affixed to the second end. The
permanent seal may be a cap non-releasably attached to the second
end. The containment tube may contain therein a biological moiety
(e.g., cells) or a therapeutic device (e.g. a cell encapsulation
member).
A third aspect relates to an implantable encapsulation device that
includes a plurality of containment tubes, each containment tube
having a first access port located at the first end of the
containment tube and a second access port located at the second end
of the containment tube. The first access ports may have thereon
resealable caps to seal the first end of the containment tubes. The
containment tubes may be interconnected at or near the second ends
by connection members. The containment tubes are independently
movable from each other and are substantially parallel to each
other along a length of the device. The containment tubes may
contain therein a biological moiety (e.g., cells) or a therapeutic
device (e.g. a cell encapsulation member). The encapsulation device
may further include a removable manifold having at least one access
port that is in fluid communication with one or more of the
containment tubes. A flush port may be fluidly connected to the
manifold by a tube.
A fourth aspect relates to an implantable encapsulation device that
includes a manifold and a plurality of containment tubes, each
containment tube having a first access port at a first end and a
second access port at a second end. The containment tubes are
affixed to the manifold at their second ends and are fluidly
connected to the manifold through the second access ports. The
manifold may be located at the first end or the second end of the
containment tubes. A resealable (or permanent) port may be located
at the opposing end of the containment tubes. The containment tubes
may be connected to each other at spaced intervals along their
lengths by one or more connection member and/or may be
substantially parallel to one another along a length of the
containment tubes. The periodically spaced intervals may be regular
(e.g., spacing is the same between connection members) or irregular
(e.g., the spacing between connection members are different). In
some embodiments, the containment tubes are stacked upon each other
in a three dimensional configuration. In yet other embodiments, the
containment tubes have a substantially planar configuration with
off-axis interconnection members. The containment tubes may contain
therein a biological moiety (e.g., cells) or a therapeutic device
(e.g. a cell encapsulation member).
A fifth aspect relates to an implantable encapsulation device that
includes at least one containment tube having a first end and a
second end and a manifold centrally located between the first end
and the second end. The manifold has at least one access port and
is fluidly connected to the at least one containment tube. In some
embodiments, the manifold includes a divider element positioned
below the at least one access port.
A sixth aspect relates to an implantable encapsulation device that
includes a laminate sheet and a plurality of containment channels
formed by adhered layers of the laminate sheet with seams
interposed between each containment channel. The plurality of
containment channels may be periodically connected to each other
via the seams along a length of the containment channels. It is to
be appreciated that access ports, manifolds, and/or flush ports may
also be included this aspect.
A seventh aspect relates to an implantable encapsulation device
that includes a manifold located at the first end or the second end
of the encapsulation device and a plurality of containment tubes
individually affixed to the manifold and in fluid communication
with the manifold. The plurality of containment tubes may be
interconnected in a non-planar arrangement. In at least one
embodiment, the containment tubes include a shape memory material
such that the containment tubes are configured to take on the
non-planar arrangement.
An eighth aspect relates to an implantable encapsulation device
that includes a single containment tube having a first end, a
second end, a point located between the first end and the second
end, a divider element, and a manifold having a single access port
positioned at the point which is centrally located between the
first and second ends of the containment tube. The divider element
enables the flow of a fluid containing cells to be divided such
that a portion of the cells flow in a first direction (e.g.,
towards the first end) and a portion of the cells flow in a second
direction (e.g., towards the second end). Alternatively, a cell
containment member (or other therapeutic device) may be placed
inside the containment tube though the access port.
A ninth aspect relates to an implantable encapsulation device that
includes a first containment tube including a first distal end and
a first proximal end having a first access port and a second
containment tube including a second distal end and a second
proximal end having a second access port, and a manifold fluidly
connected to the first access port of the first proximal end and to
the second access port of the second proximal end. The manifold
fluidly connects the first and second containment tubes.
A tenth aspect relates to an implantable encapsulation device that
includes a plurality of containment tubes having a first end and a
second end, a point centrally located between the first end and the
second end of the containment tubes, and a manifold having multiple
access ports. The manifold is in fluid connection with the
containment tubes. In some embodiments, the manifold includes
divider elements that enable the flow of a fluid containing cells
to be divided such that a portion of the cells flow in a first
direction (e.g., towards the first end) and a portion of the cells
flow in a second direction (e.g., towards the second end). It is to
be noted that cell containment members may be placed inside the
containment tubes though the access ports. In addition, the
encapsulation device could be formed of a plurality of first
containment tubes and second containment tubes connected by the
manifold.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings are included to provide a further
understanding of the disclosure and are incorporated in and
constitute a part of this specification, illustrate embodiments,
and together with the description serve to explain the principles
of the disclosure.
FIGS. 1A and 1B are schematic illustrations of cross-sections of a
cell containment member in accordance with some embodiments;
FIG. 2 is a schematic illustration of a containment tube in
accordance with some embodiments;
FIGS. 3-10 are schematic illustrations of cross-sections of a
porous polymeric material used to construct a containment tube in
accordance with some embodiments;
FIG. 11A is a schematic illustration of a containment tube having
two access ports and a flush port in accordance with some
embodiments;
FIG. 11B is a schematic illustration of a containment tube having a
single access port in accordance with some embodiments;
FIG. 12A is a schematic illustration of an encapsulation device
having a plurality of interconnected containment tubes in
accordance with some embodiments;
FIG. 12B is a schematic illustration of the encapsulation device of
FIG. 12A including a flush port and a manifold in accordance with
some embodiments;
FIG. 12C is a schematic illustration of an encapsulation device
having a plurality of containment tubes and a manifold (with a
flush port) located at a distal end thereof in accordance with some
embodiments;
FIG. 12D is a schematic illustration of an encapsulation device
having a plurality of containment tubes and a manifold (with a
flush port) located at both the distal and proximal ends thereof in
accordance with some embodiments;
FIG. 12E is a schematic illustration of an encapsulation device
that includes a manifold with a top access port on a first end and
a resealable (or permanent) port on a second end in accordance with
some embodiments;
FIG. 12F is a schematic illustration of an encapsulation device
that includes a manifold having a side access port on a first end
and a resealable (or permanent) port on a second end in accordance
with some embodiments;
FIG. 12G is a schematic illustration of an encapsulation device
that includes a manifold having a side access port at a first end,
a flush port fluidly connected to the side access port, and
resealable (or permanent) caps at a second end in accordance with
some embodiments;
FIG. 12H is a schematic illustration of an encapsulation device
that includes a manifold having a side access port on a first end
and a connection member and a port (resealable or permanent) on a
second end in accordance with some embodiments;
FIGS. 13A and B are schematic illustrations of encapsulation
devices including several individual containment tubes grouped
together as a single unit in accordance with some embodiments;
FIGS. 13C and D are schematic illustrations depicting containment
tubes connected to each other at various points along their lengths
in accordance with some embodiments;
FIG. 13E is a schematic illustration of an encapsulation device
with a resealable port at one end thereof and containment tubes
connected to each other a various points along their lengths;
FIG. 13F is a schematic illustration of an encapsulation device
with a manifold and flush port at one end thereof and containment
tubes connected to each other a various points along their
lengths;
FIG. 14A is a schematic illustration of an encapsulation device
constructed from several channels in accordance with some
embodiments;
FIG. 14B is a schematic illustration depicting a containment
channels having seams between each containment channel in
accordance with some embodiments;
FIGS. 15-17A show various three dimensional arrangements for
encapsulation devices having a plurality of containment tubes in
accordance with some embodiments;
FIG. 17B is a schematic illustration of containment tubes having a
substantially planar arrangement with off-axis interconnection
members in accordance with some embodiments;
FIG. 17C is a schematic illustration depicting a cell encapsulation
member having containment tubes fluidly connected by
interconnection members;
FIGS. 18A and 18B is a schematic illustration depicting the
variable compliance of a resealable port or manifold in accordance
with some embodiments;
FIG. 19 is a schematic illustration of a cell containment member
containing a sealing member partially positioned in an opening of a
manifold in accordance with some embodiments;
FIG. 20A shows an encapsulation device having a single containment
tube with a centrally located manifold in accordance with some
embodiments;
FIG. 20B is a schematic illustration of an encapsulation device
having two containment tubes and a centrally located manifold in
accordance with some embodiments;
FIG. 21 is a schematic illustration of an encapsulation device
having a plurality of containment tubes with a centrally located
manifold;
FIG. 22 is a schematic illustration depicting cell encapsulation
members being inserted in an encapsulation device that has been
implanted in tissue in accordance with some embodiments;
FIGS. 23-30 are schematic illustrations of encapsulation devices
containing or having thereon a bio-absorbable material in
accordance with some embodiments;
FIGS. 31A and B are schematic illustrations depicting containment
tubes connected by an access port on one end in accordance with
some embodiments;
FIGS. 32A and B are schematic illustrations containment tubes
connected by an access port on both ends in accordance with some
embodiments;
FIG. 33 is a schematic illustration depicting a cell containment
device with a center manifold in accordance with some
embodiments;
FIG. 34 is a schematic illustration depicting a cell containment
device with an off-center manifold in accordance with some
embodiments;
FIG. 35 is a schematic illustration depicting an aluminum mold
utilized in Examples 6 and 9 in accordance with some
embodiments;
FIG. 36 is a schematic illustration depicting the cell
encapsulation device formed by the method described in Example 6 in
accordance with some embodiments; and
FIG. 37 is a schematic illustration of an aluminum template
utilized in Examples 8, 9, and 10 in accordance with some
embodiments.
DETAILED DESCRIPTION
Persons skilled in the art will readily appreciate that various
aspects of the present disclosure can be realized by any number of
methods and apparatus configured to perform the intended functions.
It should also be noted that the accompanying figures referred to
herein are not necessarily drawn to scale, and may be exaggerated
to illustrate various aspects of the present disclosure, and in
that regard, the figures should not be construed as limiting. Also,
it is to be noted that the terms "containment tube" and "cell
containment tube" are used interchangeably herein. In addition, the
terms "porous polymeric membrane" and "polymeric membrane" are used
interchangeably herein. It is also to be appreciated that the term
"therapeutic device" may be used interchangeably with term "cell
containment member" herein.
The present disclosure relates to implantable encapsulation devices
that contain at least one containment tube capable of containing
therein a biological moiety or a therapeutic device containing a
biological moiety. Therapeutic devices may include a cell
encapsulation device, a drug delivery device, or a gene therapy
device. Biological moieties suitable for encapsulation and
implantation using the devices described herein include cells,
viruses, viral vectors, gene therapies, bacteria, proteins,
polysaccharides, antibodies, and other bioactive moieties. For
simplicity, herein the biological moiety is referred to as a cell
or cells, but nothing in this description limits the biological
moiety to cells or to any particular type of cell, and the
following description applies also to biological moieties that are
not cells.
The encapsulation devices include one or a plurality of containment
tubes. In encapsulation devices having one containment tube, the
encapsulation device may include the single containment tube, an
access port at both the proximal and distal end of the containment
tube, a flush port fluidly connected to the access port at the
distal end, and a resealable (or permanent) cap attached to the
proximal end of the containment tube. The flush port may also
include a resealable cap. Although resealable caps are described
herein as a means to close off and/or seal the access ports, any
resealable device (e.g., permanent caps or welded seals) may be
used to close and/or seal the access ports. Also, the term "access
port" as used herein is meant to include any opening into the
containment tube for the introduction and/or extraction of fluids,
biologic moieties, and/or therapeutic devices.
In encapsulation devices having multiple containment tubes, the
device may include a plurality of interconnected containment tubes
substantially parallel to each other along a length of the device.
As used herein, the term "substantially parallel" is meant to
describe containment tubes that extend in the same direction and do
not intersect each other. In another embodiment, the containment
tubes intersect at least once and are independently movable. The
containment tubes have an access port at the proximal end. It is to
be appreciated that the terms "proximal end" and "distal end" as
used herein with respect to members of the device are used for
convenience to describe the device, and are exemplary in nature.
For instance, a member described as being on the proximal end of
the device may equally be employed at the distal end. In some
embodiments, the containment tubes are formed of multiple layers
that balance and enhance the hoop and tensile strength of the
individual tubes. In another embodiment, the tubes are formed from
a laminate material in which strength is derived, at least in part,
to the materials forming the laminate. In at least one embodiment,
the containment tubes are independently movable from each other,
thus making the device flexible and/or compliant with tissue and/or
tissue movement. In addition the periodic separation of the tubes
can allow for tissue ingrowth around the tubes through the periodic
tube separations, thereby improving effective device surface area
for vascularization and nutrient and biomolecule exchange. The
containment tubes maximize surface area available for
vascularization relative to the device footprint in the body. For
instance, the containment tubes take advantage of the z-direction
without making the footprint larger. Additionally, there is no
significant non-usable surface are due to perimeter or distal
seals. In some embodiments, the containment tubes are configured to
house at least one therapeutic device that provides therapeutic
substances to an individual in need of treatment. In other
embodiments, the containment tubes are configured to house the
cells directly (i.e., with no therapeutic device). In some
embodiments, the cells may be microencapsulated. For instance, the
cells may be microencapsulated within a biomaterial of natural or
synthetic origin, including, but not limited to, a hydrogel
biomaterial. Additionally, the containment tubes may be fluidly
connected so that insertion of cells into one containment tube may
flow into another containment tube or so that a fluid stream may be
used to remove a therapeutic device from a containment tube. In
other embodiments, the containment tubes may be stacked three
dimensionally or have a substantially planar arrangement with
off-axis interconnection members.
The encapsulation device may also include a removable or
non-removable (e.g., permanent) manifold attached at one or both
ends of the containment tubes. It is to be noted that with respect
to the manifolds, caps, and seals described herein may be removable
or non-removable, depending on the particular situation. In some
embodiments, a flush port is fluidly connected to the manifold via
a tube. The tube may have a length that is substantially the length
of the containment tube. Fluid can be introduced into the distal
ends of the containment tubes via the flush port and manifold to
assist in the discharge or removal of the one or more therapeutic
devices from the proximal ends of the containment tubes. In another
embodiment the encapsulation device includes a single or a
plurality of containment tubes and a manifold positioned at a point
between the distal end and the proximal end of the containment
tube(s) (e.g., center or off center by a predetermined distance).
The manifold optionally includes a divider element that directs the
therapeutic device(s) or cells toward the distal end and/or the
proximal end of the containment tube. The containment tube(s) may
be configured to house one or more therapeutic device that provide
therapeutic substances. In other embodiments, the containment
tube(s) are configured to house the cells directly.
Encapsulation devices described herein may be implanted into a
patient prior to or after insertion of a therapeutic device or
cells into one or more of the containment tubes. For example, an
encapsulation device may be inserted into a patient and allowed to
vascularize such that vascular tissue grows into a vascularizing
layer of the containment tube. Then, the cells or therapeutic
device may be added to the containment tube in vivo. Alternatively,
a therapeutic device or cells may be placed within the containment
tubes prior to insertion of the encapsulation device into a tissue
bed of a patient. The encapsulation devices described herein are
also capable of explanation or removal from the patient such as if
the patient goes into remission and no longer needs the device or
the device needs to be taken out for other reasons such as a severe
immunologic response. In such a case, a new encapsulation device
may be implanted
I. Cell Containment Member
In some embodiments, a therapeutic device, such as a cell
containment member, is implemented for providing therapeutic
substances to an individual in need of treatment. It is to be
appreciated that the term "therapeutic device" may be used
interchangeably with term "cell containment member" herein. The
cell containment member is structured such that it maximizes a
proportion of cells in close proximity to a permeable membrane that
is in contact with the environment while maintaining a geometry
that is practical for implantation in a patient. As shown in FIGS.
1A and 1B, this may be accomplished by providing a cell containment
member 100 that includes a core 105 that is surrounded by a
permeable membrane 110. The space between the outer surface of the
core 105 and the inner surface of the permeable membrane 110 define
a boundary zone in which cells 115 may be contained. In some
embodiments, the cells may be microencapsulated. The cells may be
microencapsulated within a biomaterial of natural or synthetic
origin, including, but not limited to, a hydrogel biomaterial. A
maximum distance between the outer surface of the core 105 and the
inner surface of the permeable membrane 110 is sufficiently narrow
to provide conditions suitable for the survival and function of the
contained cells 115, whereby the viability of a large proportion of
the contained cells 115 is maintained. In particular, the cells 115
contained within the cell containment member 100 are able to obtain
nutrients and other biomolecules from the environment outside the
cell containment member 100 and expel waste products and
therapeutic substances outside the cell containment member 100
through the permeable membrane 110. Suitable distances to ensure
cell survival may include from about 30 microns to about 1,000
microns, from about 40 microns to about 900 microns, from about 50
microns to about 800 microns, or from about 40 microns to about 700
microns.
Any material which acts to displace cells from the center of the
cell containment member 100 is suitable for use as the material of
the core 105. For example, suitable core materials include, but are
not limited to, polytetrafluoroethylene (PTFE), expanded
polytetrafluoroethylene (ePTFE), polydimethysiloxane, polyurethane,
polyester, polyamide, or hydrogels derived from polysaccharides,
alginate, hydrolyzed polyacrylonitrile, and combinations thereof.
In some embodiments, the core is a flexible polymer or elastomer.
In other embodiments, the core may be manufactured from
polysaccharides, hydrophilic copolymers of polyacrylonitrile, a
copolymer of polyacrylonitrile and acrylamide, and/or other
non-porous polymers.
The permeable membrane may be manufactured from any biologically
compatible material having the appropriate permeability
characteristics. The permeable membrane has permeability
characteristics that permit the passage therethrough of cellular
nutrients, biomolecules, waste products, and therapeutic substances
secreted by cells contained within the device while not permitting
the passage of cells external to the cell encapsulation device.
Non-limiting examples of polymers having suitable selective
permeability and/or porous properties and which may be used as the
permeable membrane include, but are not limited to, alginate,
cellulose acetate, polyalkylene glycols such as polyethylene glycol
and polypropylene glycol, panvinyl polymers such as polyvinyl
alcohol, chitosan, polyacrylates such as
polyhydroxyethylmethacrylate, agarose, hydrolyzed polyacrylonitrile
polyacrylonitrile copolymers, polyvinyl acrylates such as
polyethylene-co-acrylic acid, porous polytetrafluoroethylene
(PTFE), modified polytetrafluoroethylene polymers,
tetrafluoroethylene (TFE) copolymers, porous polyalkylenes such as
porous polypropylene and porous polyethylene, porous polyvinylidene
fluoride, porous polyester sulfone (PES), porous polyurethanes,
porous polyesters, porous PPX (ePPX), porous ultra-high molecular
weight polyethylene (eUHMWPE), porous ethylene tetrafluoroethylene
(eETFE), porous vinylidene fluoride (eVDF), porous polylactic acid
(ePLLA), and copolymers and combinations thereof, as well as woven
or non-woven collections of fibers or yarns, or fibrous matrices,
either alone or in combination.
Various types of prokaryotic and eukaryotic cells, mammalian cells,
non-mammalian cells, and stem cells may be used with the cell
containment members and containment tubes described herein. In some
embodiments, the cells may be microencapsulated within a
biomaterial of natural or synthetic origin, including, but not
limited to, a hydrogel biomaterial. In some embodiments, the cells
secrete a therapeutically useful substance. Such therapeutically
useful substances include hormones, growth factors, trophic
factors, neurotransmitters, lymphokines, antibodies or other cell
products which provide a therapeutic benefit to the device
recipient. Examples of such therapeutic cell products include, but
are not limited to, insulin, growth factors, interleukins,
parathyroid hormone, erythropoietin, transferrin, and Factor VIII.
Non-limiting examples of suitable growth factors include vascular
endothelial growth factor, platelet-derived growth factor,
platelet-activating factor, transforming growth factors bone
morphogenetic protein, activin, inhibin, fibroblast growth factors,
granulocyte-colony stimulating factor, granulocyte-macrophage
colony stimulating factor, glial cell line-derived neurotrophic
factor, growth differentiation factor-9, epidermal growth factor,
and combinations thereof.
II. Containment Tubes
FIG. 2 shows an exemplary implantable containment tube 200 that
includes a first access port 215, a second access port 225, a
permeable membrane 205 forming the exterior of the containment tube
200, and a lumen 210 extending through the containment tube 200. In
some embodiments, the containment tube 200 is a flexible tube that
is configured to receive one or more therapeutic device that
provides therapeutic substances to an individual in need of
treatment. In accordance with some aspects of the present
disclosure, the containment tube 200 has a cross-section in a shape
that conforms or substantially conforms, at least in part, to the
form of the therapeutic device (e.g., cell containment member) the
containment tube 200 is intended to house. As non-limiting
examples, the cross-section of the containment tube 200 may be
circular, ovoid, or elliptical. In the embodiments disclosed
herein, the containment tubes may have inner diameters that range
from about 100 microns to about 5 mm, from about 150 microns to
about 4.5 mm, from about 200 microns to about 4 mm, or from about
250 microns to about 3.5 mm. In some embodiments in which multiple
containment tubes are utilized, the containment tubes may be
separated from each other a distance from about 0.1 microns to
about 3 mm, from about 5 microns to about 2.5 mm, from about 10
microns to about 2 mm, from about 25 microns to about 1.5 mm, or
from about 50 microns to about 1 mm. It is to be noted that all
ranges described herein are exemplary in nature and include any and
all values in between.
In some embodiments, the containment tube 200 is a flexible tube
configured to receive cells directly (e.g., without the presence of
a therapeutic device). The containment tube 200 is structured such
that it maximizes the number of cells in close proximity to the
permeable membrane 205 that is in contact with the environment
while maintaining a geometry which is practical for implantation in
a patient. The lumen 210 defines an area in which cells may be
contained. In addition, the lumen 210 provides conditions that are
suitable for survival and function of the contained cells. Suitable
distances to ensure cell survival may include from about 30 microns
to about 1,000 microns, from about 40 microns to about 900 microns,
from about 50 microns to about 800 microns, or from about 40
microns to about 700 microns. For example, the cells contained
within the lumen 210 of the containment tube 200 are able to obtain
nutrients and other biomolecules from the environment outside the
containment tube 200 and expel waste products and therapeutic
substances outside the containment tube 200 through the permeable
membrane 205.
The containment tube 200 is scalable in that it can easily be
configured throughout a range of diameters so that the containment
tube can be used to house cells and/or therapeutic devices with
varying shapes and sizes while ensuring survival and function of
these cells. To ensure that conditions are suitable for the
survival and function of the cells contained within the containment
tube 200, the diameter of the containment tube 200 is either
sufficiently small such that nutrients and other biomolecules are
able to reach the center of the tube 200 or a central portion of
the containment tube 200 contains a cell displacing member so that
a maximum distance between the displacing member and the wall of
the containment tube 200 is such that the viability of a large
portion of the cells is maintained. In some embodiments, cells are
introduced into the containment tube 200 in the form of a
suspension or slurry in a medium. The cells may be individual
cells, cell aggregates, or cell clusters. As one example, the
medium may be a cell culture or cell growth medium, optionally
including desired nutrients and other biomolecules. In some
embodiments, insertion of the cells into the containment tube may
be accomplished using a syringe.
In some embodiments, the permeable membrane 205 of the containment
tube 200 is made of a porous polymeric material having selective
sieving and/or porous properties. The porous polymeric material
controls the passage of solutes, biochemical substances, viruses,
and cells, for example, through the material, primarily on the
basis of size. Porous polymeric materials having suitable selective
permeability and/or porous properties useful for construction of
containment tubes as described herein include, but are not limited
to, alginate, cellulose acetate, polyalkylene glycols such as
polyethylene glycol and polypropylene glycol, panvinyl polymers
such as polyvinyl alcohol, chitosan, polyacrylates such as
polyhydroxyethylmethacrylate, agarose, hydrolyzed
polyacrylonitrile, polyacrylonitrile copolymers, polyvinyl
acrylates such as polyethylene-co-acrylic acid, porous
polytetrafluoroethylene (PTFE), modified polytetrafluoroethylene
polymers, tetrafluoroethylene (TFE) copolymers, porous
polyalkylenes such as porous polypropylene and porous polyethylene,
porous polyvinylidene fluoride, porous polyester sulfone (PES),
porous polyurethanes, porous polyesters, and copolymers and
combinations thereof. In other embodiments, the materials useful as
an outer porous layer include biomaterial textiles.
In some embodiments, the porous polymeric material may be a
bio-absorbable material. Alternatively, the porous polymeric
material may be coated with a bio-absorbable material or a
bio-absorbable material may be incorporated into or onto the porous
polymeric material in the form of a powder. Coated materials may
promote infection site reduction, vascularization, and favorable
type 1 collagen deposition. The porous polymeric materials
described herein may include any bio-absorbable material known in
the art. Non-limiting examples include, but are not limited to,
polyglycolide:trimethylene carbonate (PGA:TMC), polyalphahydroxy
acid such as polylactic acid, polyglycolic acid, poly (glycolide),
and poly(lactide-co-caprolactone), poly(caprolactone),
poly(carbonates), poly(dioxanone), poly (hydroxybutyrates),
poly(hydroxyvalerates), poly (hydroxybutyrates-co-valerates), and
copolymers and blends thereof.
In some embodiments, the bio-absorbable material may have the
capability to generate reactive oxygen species (ROS) at different
levels in the body. ROS have been shown to promote various cell
responses in the body, including, but not limited to, inhibiting or
promoting cell proliferation, differentiation, migration,
apoptosis, and angiogenesis. ROS generating materials can be made
according to the teachings set forth in, for example, U.S. Pat. No.
9,259,435 to Brown, et al.
In embodiments where the permeable membrane 205 is porous only
through a portion of its thickness, the molecular weight cutoff, or
sieving property, of the porous membrane 205 begins at the surface.
As a result, certain solutes and/or cells do not enter and pass
through the porous spaces of the material from one side to the
other. FIG. 3 shows a cross-sectional view of a porous polymeric
material 300 useful in a containment tube described herein, where
the selective permeability of the polymeric material 300 excludes
cells 305 from migrating or growing into the porous spaces of the
polymeric material 300 while permitting bi-directional flux of
solutes 310 across the thickness of the polymeric material 300.
Vascular endothelial cells can combine to form capillaries thereon.
Such capillary formation or neovascularization of the polymeric
material 300 of the containment tube permits fluid and solute flux
between tissues of a patient and the contents of a therapeutic
device to be enhanced.
In some embodiments, permeability of the polymeric material can be
varied continuously across the thickness of the polymeric material.
FIG. 4 is a cross-sectional view of a porous polymeric material 400
useful in a containment tube described herein, where the selective
permeability of the polymeric material 400 varies continuously
across the thickness of the material as indicated by the gradually
increasing density of the stippling in the figure. In some
embodiments, the permeability of the porous polymeric material 400
is varied from one cross-sectional area of the material to another
to form a stratified structure. FIG. 5 is a cross-sectional view of
a polymeric material 500 useful in a containment tube described
herein, where the selective permeability of the polymeric material
500 varies across the thickness of the polymeric material 500 as
indicated by the increasing density of the stippling in the
figure.
In some embodiments, the permeability of the porous polymeric
material is varied across its thickness with additional layers of
porous polymeric material. FIG. 6 is a cross-sectional view of a
porous polymeric material 600 useful in a containment tube
described herein, where the selective permeability of the polymeric
material 600 is varied across the thickness of the polymeric
material 600 with one or more additional layers of porous polymeric
material 605. The additional layers of porous polymeric material
605 may have the same composition and permeability as the initial
layer of porous polymeric material 600 or the one or more
additional layers 605 may have a different composition and/or
permeability.
In another embodiment, the selective permeability of the porous
polymeric material is varied by impregnating the void spaces of the
porous polymeric material with a hydrogel material. A hydrogel
material can be impregnated in all or substantially all of the void
spaces of a porous polymeric material (e.g., pores of a porous
membrane) or in only a portion of the void spaces. For example, by
impregnating a porous polymeric material with a hydrogel material
in a continuous band within the polymeric material adjacent to
and/or along the interior surface of the porous polymeric material,
the selective permeability of the porous polymeric material is
varied from an outer cross-sectional area of the porous polymeric
material to an inner cross-sectional area of the porous polymeric
material. FIG. 7 is a cross-sectional view of a porous polymeric
material 700 useful in a containment tube described herein, where
the selective permeability of the polymeric material 700 is varied
across the thickness 705 of the polymeric material 700 with a
hydrogel material 710.
The amount and composition of hydrogel material impregnated into
the porous polymeric material depends in large part on the
particular porous polymeric material used to construct an
apparatus, the degree of permeability required for a given
application, and the biocompatibility of the hydrogel material.
Non-limiting examples of useful hydrogel materials for use in the
present invention include, but are not limited to, hydrolyzed
polyacrylonitrile, alginate, agarose, carrageenan, collagen,
gelatin, polyvinyl alcohol, poly(2-hydroxyethyl methacrylate),
poly(N-vinyl-2-pyrrolidone), polyethylene glycol,
polyethyleneimine, fibrin-thrombin gels, or gellan gum, and
copolymers thereof, either alone or in combination. In certain
aspects of the present invention, the total thickness of an
expanded PTFE/hydrogel composite may range from about 2 .mu.m to
about 1000 .mu.m.
In yet other embodiments, the permeability of the porous polymeric
material can be varied across the thickness of the polymeric
material with an additional layer of porous polymeric material and
a further layer of hydrogel material. FIG. 8 is a cross-sectional
view of a porous polymeric material 800 useful in a containment
tube described herein, where the selective permeability of the
polymeric material 800 is varied across the thickness 805 of the
polymeric material 800 with an additional layer of porous polymeric
material 810 and a further layer of a hydrogel material 815. An
advantage of this embodiment is the additional protection provided
an implant patient against contamination with cells from a failed
containment tube or cell containment member described herein. In
addition, this configuration will provide a strong cell and humoral
immunoisolation barrier.
In some embodiments, the permeability of the porous polymeric
material is selected to permit growth of cells from a patient into,
but not through, the polymeric material. In one or more embodiment,
a cell permeable zone is formed in the void spaces of a porous
polymeric material starting at the exterior surface of the
polymeric material and continuing to a point within the polymeric
material adjacent to the interior surface of the cell containment
tube where the permeability of the porous polymeric material to
cells is decreased so that cells that have migrated into the void
spaces of the polymeric material cannot migrate further and
penetrate the interior surface of the polymeric material. FIG. 9
depicts a cross-sectional view of a porous polymeric material 900
useful in a containment tube described herein, where the polymeric
material 900 includes a cell permeable zone 905 beginning at the
exterior surface 910 of the polymeric material 900 and continuing
across the thickness of the polymeric material 900 to a cell
exclusion zone 915 within the polymeric material 900 adjacent to
and continuous with the interior surface 920 of the polymeric
material 900.
The region of the porous polymeric material in which cells cannot
migrate or grow is referred to as a cell exclusion zone and is
impervious to cellular ingrowth. A cell exclusion zone prevents or
minimizes invasive cells from entering the lumen of the containment
tube and contacting, adhering to, fouling, ingrowing, overgrowing,
or otherwise interfering with a therapeutic device or cells
contained within the containment tube. To exclude invading host
cells from growing through to the interior surface of the
containment tube, the pore size of the cell exclusion zone may be
less than about 5 microns, less than about 1 micron, or less than
about 0.5 microns, as measured by porometry. In some embodiments,
the permeability of the polymeric material may be adjusted with a
hydrogel material.
In some embodiments, the permeable membrane is a composite material
or laminate that includes an outer porous polymeric layer and an
inner porous polymeric layer disposed adjacent to the outer porous
polymeric layer. The inner and outer porous polymeric layers have
different porosities, and may include or be formed of the same
material or different materials. In some embodiments, the inner
porous layer has a porosity that is less than the porosity of the
outer porous layer. Portions of the inner porous polymeric layer
form the interior surface of the containment tube.
The inner porous polymeric layer is impervious to cellular or
vascular ingrowth, and is sometimes referred to as a cell retentive
layer or a tight layer. In some embodiments, the inner porous layer
has an average pore size that is less than about 5 microns, less
than about 1 micron, or less than about 0.5 microns, as measured by
porometry. In some embodiments, the pores resist cellular ingrowth
but are selectively permeable to macromolecules.
The outer porous layer has an average pore size that is large
enough to permit growth of vascular tissue from a patient into the
pores of the outer porous polymeric layer. This layer may be
referred to as a vascularizing or an open layer. In some
embodiments, the pore size of the outer porous polymeric layer is
greater than about 5.0 microns, as measured by porometry. Ingrowth
of vascular tissues through the outer porous layer facilitates
nutrient and other biomolecule transfer from the body to the cells
encapsulated in the containment tube.
Optionally, the containment tube may include only the outer porous
polymeric material, or a laminate formed of multiple porous
polymeric materials, where each porous polymeric material has
sufficient porosity to permit growth of vascular tissue from a
patient into the pores of the polymeric material. As such, growth
of vascular tissue is permitted through the entire thickness of the
polymeric material(s) forming the containment tube.
Various cell types can grow into the cell permeable zone
vascularizing (open) layer of a porous polymeric material of a
containment tube as described herein. The predominant cell type
that grows into a particular porous polymeric material depends
primarily on the implantation site, the composition and
permeability of the material, and any biological factors, such as
cytokines and/or cell adhesion molecules, for example, that may be
incorporated in the material or introduced through the containment
tube. In some embodiments, vascular endothelium is the predominant
cell type that grows into a porous polymeric material for use in a
containment tube. Vascularization of the porous polymeric material
by a well-established population of vascular endothelial cells in
the form of a capillary network is encouraged to occur as a result
of neovascularization of the material from tissues of a patient
into and across the thickness of the material very close to the
interior surface of the apparatus, but not across the cell
exclusion zone or cell retentive (or tight) layer.
FIG. 10 is a cross-sectional view of a porous polymeric material
1000 useful in a containment tube described herein, where the
polymeric material 1000 includes a cell permeable zone 1005
beginning at the exterior surface 1010 of the polymeric material
1000 and continuing across the thickness of the polymeric material
1000 to a cell exclusion zone 1015 within the polymeric material
1000 adjacent to and continuous with the interior surface 1020 of
the polymeric material 1000. The cell permeable zone 1005 is
populated with vascular structures 1025. Vascularization can occur
without the addition of biological factors and/or, angiogenic
factors, which can be used to enhance vascularization of the
containment tube. In addition, angiogenesis can be stimulated by
conditions, such as hypoxia. The neovascularization of a
containment tube improves mass transport of therapeutic drugs or
biochemical substances between the interior surface of the
containment tube and tissues of a patient, thereby enhancing the
quantity and rate of transport of therapeutic drugs or biochemical
substances between the contents of a therapeutic device housed in
the containment tube and tissues of the patient.
In some embodiments, the encapsulation device is implanted into a
patient in a configuration similar to or dissimilar to its final
configuration, but for the encapsulation device to assume its final
shape, some migration of the implanted encapsulation device may
occur. Vascularization and other tissue ingrowth of the cell
permeable zones of the containment tubes as described herein can
anchor the encapsulation device at the implantation site. This
anchoring, however, does not prevent the transformation of the
encapsulation device into its primary shape because shape changes
of the device occur shortly after implantation and before
significant vascularization and other tissue growth occurs. The
shape transformation may be a result of significant forces exerted
by a shape memory element or by the manifold joining the ends of
the containment tubes. The anchoring minimizes or prevents the
encapsulation device from moving from the implantation site over
time and once sufficient anchoring has occurred, can assist the
encapsulation device in maintaining its shape. Maintaining the
shape of a containment tube as described herein is often necessary
for easy placement, replacement, and proper functioning of the
cells contain contained in the cell containment tube(s) within the
encapsulation device.
In some embodiments, the containment tube includes a shaping
element. The shaping element can be configured to induce the
containment tube into a more compliant structure such as a curved
or wavy shape, such as a generally toroidal configuration, in a
tissue bed. In some embodiments, the shaping element may also hold
the containment tube in a desired shape during implantation and
subsequent use. Non-limiting examples of useful shaping elements
include windings, strips, spline, stents, and combinations thereof.
The shaping elements may be on the exterior surface of the conduit
of the containment tube, between the layers of the conduit or along
the interior surface of the conduit. In one embodiment, the shaping
element provides the ability to insert the containment tube in any
configuration convenient for insertion, and once inserted the
containment tube independently assumes a preferred in-use
configuration. In another embodiment, a shaping element holds the
containment tube in a preferred configuration in use such that
therapeutic devices can easily be removed from and inserted into
the containment tube.
In some embodiments, the shaping element includes a shape memory
material or structure made therefrom. Non-limiting examples of
useful shape memory materials include shape memory alloys, such as
nitinol, and shape memory polymers such as polyetheretherketone,
polymethyl methacrylate, polyethyl methacrylate, polyacrylate,
poly-alpha-hydroxy acids, polycaprolactones, polydioxanones,
polyesters, polyglycolic acid, polyglycols, polylactides,
polyorthoesters, polyphosphates, polyoxaesters, polyphosphoesters,
polyphosphonates, polysaccharides, polytyrosine carbonates,
polyurethanes, polyurethanes with ionic or mesogenic components
made by a pre-polymer method, and copolymers or polymer blends
thereof. Other block copolymers also show the shape-memory effect,
such as, for example, a block copolymer of polyethylene
terephthalate (PET) and polyethyleneoxide (PEO), block copolymers
containing polystyrene and poly(1,4-butadiene), and an ABA triblock
copolymer made from poly(2-methyl-2-oxazoline) and
polytetrahydrofuran. Non-limiting shape memory alloys include, but
are not limited to, copper-aluminum-nickel, copper-zinc-aluminum,
and iron-manganese-silicon alloys. In addition to inducing the
containment tube into a desired (pre-determined) configuration in
use, the shape memory element facilitates implantation, including
facilitating any change in profile of the containment tube during
implantation.
Many of the materials used to construct a containment tube as
described herein are inherently radio-opaque. Those materials that
are not inherently radio-opaque can be modified to be radio-opaque
by impregnation of the material with barium, for example. Other
useful methods for rendering a material radio-opaque are known to
those skilled in the art. The radio-opacity of materials used to
construct a containment tube as described herein is mainly used to
facilitate surgical placement of the containment tube or to locate
the containment tube in a patient following implantation.
In some embodiments, a containment tube as described herein
maintains a consistent cylindrical cross-section for containing
cells or a generally cylindrically shaped therapeutic device (e.g.,
a cell containment member). In some tubular embodiments, open ends
of the tube can be prevented from collapsing with a stent. The
stent can be in any shape and made of any biocompatible material
useful for keeping all or part of tubular containment tube in an
opened, or expanded, tubular form during storage and/or following
implantation. Useful materials for a stent include, but are not
limited to, stainless steel, titanium, and hydrogels. To maintain
the containment tube in an expanded configuration when a
therapeutic device (e.g., cell containment member) is not inserted
or no cells are present, an inert core simulating the shape and
resilience of a therapeutic device may be placed in the containment
tube. A cell encapsulation device as described herein may be
implanted into a patient prior to or after insertion of a
therapeutic device or cells into one or more of the containment
tubes. For example, an encapsulation device may be inserted into a
patient and allowed to vascularize such that vascular tissue grows
into a vascularizing layer of the cell containment tube. The cells
or therapeutic device may then be added to the containment tubes in
vivo. Alternatively, a therapeutic device or cells may be placed
within the containment tubes prior to insertion of the
encapsulation device into a tissue bed of a patient.
III. Encapsulation Device with One Containment Tube
FIG. 11A depicts an encapsulation device 1100 containing a single
containment tube 1105 in accordance with at least one embodiment.
The encapsulation device 1100 may include a containment tube 1105,
a first access port 1150 at a proximal end 1115, a second access
port 1140 at a distal end 1110, a flush port 1120 fluidly connected
to the second access port 1140 port via a tube 1135 and a
connection member 1130. A resealable cap 1125 may be attached to
the proximal end 1115 of the containment tube 1105. The flush port
1120 may also include a resealable cap 1160. Although resealable
caps are described herein as a means to close off and/or seal the
access ports, any resealable device may be used. In alternative
embodiments, the encapsulation device 1100 may have a resealable
cap 1125 at the distal end 1110 and a connection member 1130 at the
proximal end 1115 (not illustrated). In other embodiments, the
encapsulation device 1100 may have a resealable cap 1125 at both
the proximal end 1115 and the distal end 1110 (not illustrated). In
yet other embodiments, the encapsulation device 1100 has a flush
port 1120 at both the proximal end 1115 and the distal end 1110
(not illustrated).
The second access port 1150 provides an access point through which
cells and/or one or more therapeutic device may be moved in and out
of the luminal region of the containment tube 1105. The flush port
1120 provides an access point through which a fluid stream can be
delivered to the luminal region of the containment tube 1105 to
fill and/or flush the luminal region of the containment tube 1105.
In some embodiments, the fluid stream can be used to fill the
luminal region with cells. In other embodiments, the fluid stream
can be used to push the one or more therapeutic devices or cells
from the luminal region of the containment tube 1105 through the
second access port 1150 to an area external to the containment tube
1105.
As discussed above, the flush port 1120 is in fluid communication
with the containment tube 1105 via the tube 1135. In some
embodiments, the tube 1135 is constructed of a biocompatible
material having a length that is substantially equal, such as
within 1 cm, to a length of the containment tube 1105 such that a
proximal end of the tube 1135 with the resealable cap 1160 resides
near or adjacent to the proximal end 1115 of the containment tube
1105 (and/or near to the proximal end of the encapsulation device
1100) when the encapsulation device 1100 is implanted in a patient.
In embodiments in which the encapsulation device 1100 has a flush
port at both the proximal end 1115 and the distal end 1110 of the
containment tube 1105, the access port on either the proximal end
or the distal end of the containment tube can be used to provide an
access point through which cells and/or one or more therapeutic
device may be moved in and out of the luminal region of the
containment tube (not illustrated). The containment tube 1105 may
be constructed with a composite material having a cell retention
layer and vascularizing layer as described herein.
The resealable caps 1125, 1160 and the connection fitting 1130 are
secured to the porous polymeric material forming the containment
tube 1105. Commercially available fittings, such as Luer-lok
connectors can also be used as a resealable cap 1125, 1160. In some
embodiments, one or more of resealable caps 1125,1160 and/or
connection fitting 1130 is a hollow cylindrically shaped fitting
having a first portion that fits snugly inside an end of the
containment tube 1105 and a second portion that extends beyond the
end of the containment tube 1105 to receive and retain a sealing
element. In some embodiments, the resealable caps 1125,1160 and
connection fitting 1130 may be fabricated by injection molding a
fitting onto the end of the containment tube 1105 using techniques
known to those skilled in the art. In some embodiments, the
resealable cap 1125 is a hole in the containment tube 1105 with one
or more flexible pieces, or flaps, of porous polymeric material
positioned to cover and close the hole. The flaps may be formed as
part of the encapsulation device 1100 or may be attached to the
encapsulation device 1100 subsequent to its construction.
The resealable caps 1125, 1160 and connection fitting 1130 can be
repeatedly opened and closed with a seal. As used herein, a seal
includes, but is not limited to, caps, plugs, clamps, compression
rings, or valves. The seal may be attached to the resealable caps
1125, 1160 and connection fitting 1130 with friction, by clamping,
or with a screw comprised of threads and grooves. Depending on the
intended use of the encapsulation device 1100, the caps 1125, 1160
and connection fitting 1130 are sealed to create a hermetical seal,
a fluid-tight seal, or a non-fluid-tight seal. An encapsulation
device 1100 intended for life-time or long term (e.g., at least
about three weeks) implantation in a patient, may be sealed with a
hermetical or a fluid-tight seal.
The flush port 1120 and tube 1135 may have any shape suitable for
facilitating filing and flushing of the luminal region of the
containment tube 1105. In some embodiments, the flush port 1120 and
tube 1135 are aligned in a same horizontal plane as the cell
containment tube 1105 (as shown in FIG. 11A). In some embodiments,
the tube 1135 may have an elbow or angle (e.g., 30.degree.,
45.degree., or 90.degree.) such that the tube 1135 and flush port
1120 extend through the horizontal plane of the cell containment
tube 1105 (not shown).
In accordance with some embodiments, a therapeutic device (e.g.,
cell containment member) may be housed within the containment tube
1105. In some embodiments, the therapeutic device is designed to
seal with an interface of the resealable cap 1125 or the connection
fitting 1130. In some embodiments, the therapeutic device includes
a grasping structure (e.g., a tab) such that a clinician can hold
the grasping structure to hold or manipulate (e.g., insert or
remove) the therapeutic device from within the containment tube.
Additionally, the therapeutic device can be repeatedly attached and
detached with a seal to the resealable cap 1125 or connection
fitting 1130 such that the therapeutic device can be inserted and
retrieved from the containment tube 1105. In some embodiments, the
therapeutic device is removed and a new therapeutic device
inserted. It is to be appreciated that not only is the therapeutic
device removable, but also the encapsulation device 1100.
FIG. 11B illustrates a containment tube 1105 that has a single
access port 1150 at a proximal end 1115 and a permanent cap 1145
(or seal) at the distal end 1110. In the embodiment depicted in
FIG. 11B, a resealable cap 1125 is used to close or seal the access
port 1150 when not in use. In some embodiments, the distal end 1110
of the containment tube 1105 is simply the closed end of the
containment tube (and therefore no cap is needed to seal the end).
As with the embodiment described above, a therapeutic device can be
housed within the containment tube 1105 and may inserted into the
tube 1105 through the access port 1150. In addition, the
therapeutic device can be accessed and/or retrieved from the
containment tube 1105 via the access port 1150.
IV. Encapsulation Device with Multiple Containment Tubes
FIG. 12A depicts an encapsulation device containing multiple
containment tubes in accordance with at least one embodiment. As
shown, the encapsulation device 1200 includes a plurality of
interconnected containment tubes 1205 that are substantially
parallel to each other along a length of the device 1200. Each
containment tube 1205 has a first access port 1270 at a proximal
end 1210 and a second access port 1297 at a distal end 1215. The
second access ports 1297 may have thereon resealable caps 1250 to
seal the distal ends of the containment tubes 1205. Although not
depicted, resealable caps may also be affixed to the first access
ports 1270 to seal the proximal ends of containment tubes 1205. The
containment tubes 1205 may be interconnected at connection members
1260 at their proximal ends. The connection members 1260 may be
made of the porous polymeric material(s) forming the containment
tubes 1205 or be made of a different polymeric and/or other
biocompatible material. Although not depicted, a flush port may be
fluidly connected to one or more containment tube(s) 1205 to fill
and/or flush the luminal region of the containment tube(s) 1205 in
a manner such as described above with reference to FIG. 11A. In
some embodiments, the therapeutic device(s) is removed from the
containment tube(s) 1205 and a new therapeutic device inserted. It
is to be appreciated that not only are the therapeutic devices
removable, but also the encapsulation device 1200.
In the embodiment depicted in FIG. 12A, the containment tubes 1205
are independently movable from each other, thus making the device
1200 flexible and/or compliant with tissue and/or tissue movement.
The containment tubes 1205 may be configured to house at least one
therapeutic device. Alternatively, the containment tubes 1205 may
be configured to house cells (or other biological moieties)
directly. In some embodiments, the containment tubes 1205 may be
fluidly connected, such as by the connection members 1260 and/or by
a flush port 1255 connected to a manifold 1235 via a tube 1240 (see
FIG. 12B) so that insertion of cells into one containment tube may
flow into another containment tube or so that a fluid stream may be
applied to the containment tubes 1205 to remove a therapeutic
device from a containment tube. In some embodiments, a new
therapeutic device is inserted into the containment tube. Once
filled, the manifold 1235 may be removed and the containment tubes
sealed. As discussed above, a seal includes, but is not limited to,
caps, plugs, clamps, compression rings, or valves. It is to be
noted that the embodiment depicted in FIG. 12B is less compliant
(more stiff) than the embodiment of FIG. 12A due to the inclusion
of the manifold 1235.
Turning to FIG. 12C, an encapsulation device 1200 may include a
plurality of containment tubes 1205 having first access ports (not
illustrated) at a distal end 1210, second access ports (not
illustrated) at a proximal end 1215, a resealable port 1225 sealing
the second access ports, and a manifold 1235 fluidly connecting the
first access ports at the distal end 1210. A flush port 1255 may be
fluidly connected to the manifold 1235 via a tube 1240. When not in
use, a resealable cap 1245 may cover and seal the flush port
1255.
The second access ports provide access points through which one or
more therapeutic device (e.g., cell containment member) may be
moved in and out of the luminal regions of the containment tubes
1205. The first access ports provide access points through which a
fluid stream can be delivered to the luminal region of the
containment tubes 1205 to fill and/or flush the luminal region of
the plurality of containment tubes 1205. In some embodiments, the
fluid stream can be used to fill the luminal region of the
containment tubes 1205 with cells, or remove cells from the luminal
region. In other embodiments, the fluid stream can be used to push
the one or more therapeutic device (e.g., cell containment member)
from the luminal regions of the containment tubes 1205 through
unsealed first access ports to an area external to the containment
tubes 1205. It is to be appreciated that a plurality of containment
tubes 3105 may be fluidly connected to each other by a single
access port 3110 at one end of the encapsulation device 3100, such
as is shown in FIGS. 31A and B, or by an access port 3210, 3220 at
both ends of the containment tubes 3205 of the encapsulation device
3200 shown in FIGS. 32A and B.
Turning back to FIG. 12C, the manifold 1235 is constructed of a
biocompatible material and includes at least one connection port
1275 in fluid communication with the tube 1240 and flush port 1255.
The manifold 1235 further includes a chamber (not depicted) having
one or more openings therein such that the manifold 1235 is in
fluid communication with the second access ports and with the
luminal region of each of the containment tubes 1205. In
embodiments in which the chamber includes a plurality of openings,
each of the openings of the manifold 1235 is aligned with the
access port of each of the containment tubes 1205.
In some embodiments, the flush port 1255 and tube 1240 may be
aligned in a same horizontal plane as the containment tubes 1205
(as shown in FIG. 12C). In other embodiments, the tube 1240 may
have an elbow or angle (e.g., 30.degree., 45.degree., or
90.degree.) such that the tube 1240 extends through the horizontal
plane of the containment tubes 1205 (not shown). The plurality of
containment tubes 1205 may be individually affixed (e.g.,
permanently bonded or resealable) to an end of the manifold 1235
and movable as a group.
In some embodiments, the containment tube 1240 is constructed of a
biocompatible material having a length that is substantially equal
to a length of the containment tubes 1205 such that a proximal end
of the containment tube 1240 with the resealable cap 1245 resides
near or adjacent to the proximal end of the containment tubes 1205
(and/or at or near the proximal end 1215 of the encapsulation
device 1200), particularly when the encapsulation device is
implanted in a patient. In some embodiments, the containment tubes
1205 may be constructed with a composite material having a cell
retention layer and vascularizing layer as described herein.
The resealable port 1225 can have any shape suitable for
facilitating placement, retrieval, and replacement of one or more
cell containment member in the luminal regions of the containment
tubes 1205. In some embodiments, the resealable port 1225 is a
hollow fitting (e.g., made of PTFE) having a first portion that
fits snugly inside ends of the containment tubes 1205 and a second
portion that extends beyond the ends of the containment tubes 1205
to receive and retain a sealing element. In some embodiments, the
resealable port 1225 can be fabricated by injection molding of a
fitting onto the ends of the containment tubes 1205 using
techniques known to those skilled in the art.
Additionally, the resealable port 1225 and flush port 1255 can be
repeatedly opened and closed with a seal. As discussed above, the
seal includes, but is not limited to, caps, plugs, clamps,
compression rings, or valves. The seal may be attached to the
resealable port 1225 with friction, by clamping, or with a screw
comprised of threads and grooves. Depending on the intended use of
the encapsulation device 1200, the resealable port 1225 and/or
flush port 1255 is sealed to create a hermetical seal, a
fluid-tight seal, or a non-fluid-tight seal. An encapsulation
device 1200 intended for permanent or long term (e.g., at least
about three weeks) implantation in a patient, may be sealed with a
hermetical or a fluid-tight seal.
In an alternate embodiment depicted in FIG. 12D, the encapsulation
device 1200 has first manifold 1235 fluidly connecting the first
access ports at the distal end 1210 and a second manifold 1260
fluidly connecting the second access ports at the proximal end
1215. The first and second manifolds 1235, 1260 are fluidly
connected to a first flush port 1255 and a second flush port 1265,
respectively, by tube 1240 and tube 1270. When not in use,
resealable caps 1245, 1270 may cover and seal the flush ports 1255,
1265. The access ports on either the proximal end 1215 or the
distal end 1210 can be used to provide an access point through
which one or more cell containment member (or other therapeutic
device) or cells may be moved in and out of the luminal regions of
the containment tubes 1205.
FIG. 12E-12G depict various manifolds and seals that may be used in
conjunction with encapsulation devices described herein. For
instance, FIG. 12E depicts an encapsulation device 1201 that
includes a manifold 1280 having a top connection port 1285,
containment tubes 1205 configured so as to be fluidly connected to
the manifold 1280, a resealable connector member 1290 containing
access ports 1297, and resealable caps 1298 configured to seal the
proximal end of the resealable connector member 1290. The
connection port 1285 on either the manifold 1280 or the access
ports 1297 on the resealable connector member 1290 can be used to
provide an access point through which one or more cell containment
member (therapeutic device) or cells may be moved in and out of the
luminal regions of the containment tubes 1205.
FIG. 12F depicts an encapsulation device 1202 that includes a
manifold 1280 having a side connection port 1285, containment tubes
1205 configured so as to be fluidly connected to the manifold 1280,
and a resealable port 1204. The connection port 1285 on the
manifold 1280 or access ports 1297 on the containment tubes 1205
can be used to provide an access point through which one or more
cell containment member (or other therapeutic device) or cells may
be moved in and out of the luminal regions of the containment tubes
1205.
FIG. 12G depicts an encapsulation device 1203 that includes a
manifold 1280 having a side connection port 1285 and flush port
1262 attached thereto via a tube 1257, containment tubes 1205
configured so as to be fluidly connected to the manifold 1280,
resealable caps 1298 for sealing the proximal end 1215 of the
containment tubes 1205, and a resealable cap 1258 for sealing the
flush port 1262. The flush port 1262 or access ports 1208 on the
containment tubes 1205 can be used to provide an access point
through which one or more cell containment member (or other
therapeutic device) or cells may be moved in and out of the luminal
regions of the containment tubes 1205. In some embodiments, a
connector member may be positioned between the containment tubes
and the resealable caps (not depicted).
FIG. 12H depicts an encapsulation device 1204 that includes a
manifold 1280 having a side connection port 1285, containment tubes
1205 configured so as to be fluidly connected to the manifold 1280,
a connector member 1290 (resealable or permanent), and a resealable
port 1204. The connection port 1285 on the manifold 1280 or access
ports 1297 on the connector member 1290 can be used to provide an
access point through which one or more cell containment member (or
other therapeutic device) or cells may be moved in and out of the
luminal regions of the containment tubes 1205. In such an
embodiment, the manifold 1280 may be used to provide a fluid stream
to flush the cell containment member(s) out of the containment
tubes 1205.
Turning to FIGS. 13A, B, and C, in some embodiments, an
encapsulation device 1300 can be constructed from several
individual containment tubes 1305 grouped together as a single
unit. The individual containment tubes 1305 may or may not be
fluidly or physically connected with one another. In some
embodiments, the containment tubes are connected to each other
through connection members. As pictorially shown in FIGS. 13C and
D, the containment tubes 1305 may be connected to each other by
connection members 1375 that are periodically spaced along the
length of the containment tubes 1305 a distance 1320 from each
other. The distance 1320 may be the same or different between the
connection members 1375. Thus, the periodic spacing may have a
regular pattern (e.g., same distance between connection members) or
an irregular pattern (e.g., different distances between connection
members). It is to be appreciated that FIGS. 13C and D are included
herein to visualize the connection members 1375, and that with
further preparation, a manifold(s), a resealable port(s), a flush
port(s), resealable caps, etc. could be added to the containment
tubes 1305.
The attachment of the containment tubes 1305 by the connection
members 1375 permit the cell encapsulation device to have
flexibility at least between the connection members 1375, while at
the same time allowing for stability during implantation. In
addition, the separation of containment tubes 1305 in between the
connection members 1375 helps the host tissue to integrate fully
around and in between the containment tubes 1305. Additionally, the
space between the containment tubes 1305 maximizes surface area of
tube available for vascularization. The terms "flexible" and
"flexibility", as used herein, are meant to describe overall
compliance or bending stiffness of the cell encapsulation device
and compliance of the host interface/ingrowth layers in contact
with the host tissue, such that those ingrowth layers match the
compliance of the host tissue as well as the compliance of the cell
encapsulation device relative to the host tissue such that the cell
encapsulation device can flex and move with the host tissue without
an excessive inflammatory response due to a significant mismatch in
the compliance of the device and host interface/ingrowth layers
with the host tissue.
In some embodiments, the connection members 1375 may be formed of,
or include, a bio-absorbable material. The bio-absorbable material
degrades and resorbs into the body after the cell encapsulation
device 1300 is placed in the body. There should be little or no
degradation prior to implantation. In some embodiments only a
portion of the connection members 1374 is formed from the
bio-absorbable material, such that when the bio-absorbable material
resorbs, the cell encapsulation device 1300 retains some structure
for housing the cells or therapeutic devices within the containment
tubes 1305. In other embodiments, the bio-absorbable material makes
up all, or substantially all, of the connection members 1375 such
that no connection members 1375 remain after the bio-absorbable
material resorbs. By re-absorbing the connection members 1375, the
containment tubes 1305 are no longer restrained and are
independently movable. As discussed above, the separation of the
containment tubes 1305 helps the host tissue to integrate fully
around and in between the containment tubes, and maximizes surface
area of tube available for vascularization. Additionally, the lack
of connection members 1375, either deliberately or through
bio-absorption enables an easier removal of the cell encapsulation
device. For instance, growth of tissue onto and/or into the
connection members 1375 can act as a barb and hinder or restrict
the ease of explant/removal of the cell encapsulation device.
The bio-absorbable material may fully resorb quickly (e.g., in only
a few days or months) or may require significantly longer (e.g.
years) to fully resorb. The resorption rate of the bio-absorbable
material depends on the identity of the material and the biological
environment and can be selected by a person skilled in the art as
needed. The bio-absorbable material may be formed as a solid
(molded, extruded, or crystals), a coating (e.g. on the containment
tubes), a self-cohered web, a raised webbing, or a screen.
Advantageously, certain bio-absorbable materials provide a slow
bio-absorption profile that can be used to instruct vascularization
and other tissue ingrowth into the connection members at the
implantation site. For example, the bio-absorption profile may be
slower than the rate of vascularization. In addition, a slow
degradation profile may allow for ease of explant/removal of the
cell encapsulation device.
FIG. 13E schematically depicts a resealable port 1365 at a proximal
end 1314 of the cell encapsulation device 1390. It is to be
appreciated that a resealable port (not depicted) or resealable
caps may be affixed to the distal end of the cell encapsulation
device 1390 to seal the access ports of the containment tubes 1305
located at the distal end. FIG. 13E depicts the use of resealable
caps 1307 for ease of illustration. FIG. 14F schematically depicts
a removable manifold 1335 to fluidly connect the access ports of
the containment tubes 1305 of the cell encapsulation device 1395. A
flush port 1380 may be fluidly connected to the manifold 1335 via a
tube 1337. When not in use, a resealable cap 1385 may cover and
seal the flush port 1380. It is to be appreciated that a resealable
port (not depicted) or resealable caps may be affixed to the distal
end of the cell encapsulation device 1390 to seal the access ports
of the containment tubes 1305 located at the distal end. FIG. 13F
depicts the use of resealable caps 1307 for ease of illustration.
The distance between connection members 1375 may be from 0.25 mm to
about 10 cm, from about 0.50 mm to about 8 cm, from about 0.75 mm
to about 5 cm, from about 1 mm to about 2 cm. It is to be noted
that these distances are applicable to each of the embodiments
described herein where containment tubes and/or channels are
interconnected. In some embodiments, the individual containment
tubes 1305 can be fully connected to each other along their entire
lengths for a least compliant, or stiff, arrangement (not
depicted). The access ports 1315 may be used to move one or more
cell containment member (therapeutic device) or cells in and out of
the luminal regions of the containment tubes 1305.
Turning to FIG. 13B, a removable manifold 1335 may be used to
fluidly connect the access ports 1315 at the distal end 1312 of the
encapsulation device 1300. A flush port 1355 may be fluidly
connected to the manifold 1335 via a tube 1340. When not in use, a
resealable cap 1345 may cover and seal the flush port 1355. The
access ports 1315 provide access points through which a fluid
stream can be delivered to the luminal region of the containment
tubes 1305 to fill the luminal region of the containment tubes
1305. In some embodiments, the fluid stream can be used to fill the
luminal region of the containment tubes 1305 with cells. In some
embodiments, and as shown in FIGS. 13A and B, the containment tubes
1305 are encompassed or overmolded with a biocompatible material
1310 around their periphery to hold the containment tubes in a
tight, permanent configuration. In some embodiments, the
containment tubes 1305 may be constructed with a composite material
having a cell retention layer and vascularizing layer as described
herein. In some embodiments a woven or non-woven textile or knit
may be overlayed on the cell encapsulation device 1300. In another
embodiment, the woven or non-woven textile or knit may be
periodically attached to the cell encapsulation device 1300. The
woven or non-woven textile or knit may serve as a restraining layer
and may aid in tissue ingrowth or attachment. In addition, the
woven or non-woven textile or knit may provide mechanical support
for handleability, implantation, and removal of the cell
encapsulation device.
Turning now to FIGS. 14A and B, an encapsulation device 1400 may be
constructed from a laminate formed by adhering several layers of a
polymeric material(s) together. The layers of polymeric material
used to form the laminate may be the same layers of polymeric
material used to construct the containment tubes as described
herein, and may be constructed with a composite layer that has a
cell retention layer and vascularizing layer as described herein.
The cell encapsulation device 1400 contains containment channels
1405 with seams 1410 interposed between each containment channel
1405. The containment channels 1405 may be connected with one
another such that each containment channel is separate and fluidly
isolated from the other containment channels, such as is
pictorially depicted in FIG. 14B. Alternatively, or in addition to,
the containment channels 1405 may be connected with one another
such that the containment channels are in fluid communication with
one another. For example, the channels 1405 can be connected to
each other along their entire lengths to fluidly isolate each of
the channels from one another, or the containment channels 1405 may
be interconnected to each other at spaced (or varying) intervals
along their lengths to provide interconnection channels to fluidly
connect adjacent containment channels (not depicted). Some
containment channels may be isolated from each other while some
adjacent containment channels may be fluidly connected at one or
more point along their lengths (not depicted). In some embodiments
where the layers of material are adhered, porosity may be
maintained to allow for tissue attachment and/or vascularization
within the seams 1410.
In other embodiments, the seams 1410 may include unattached regions
between the adjacent containment channels 1405 to allow for tissue
attachment and/or vascularization. The containment channels 1405
may be sealed at one or both ends by adhering the layers of
material at the one or both ends. In some embodiments, the layers
of material are over-molded with silicone 1420 around the
periphery. In one embodiment, a manifold 1425 may be fluidly
connected to the containment channels 1405 to provide access to the
lumens of the channels for the placement of cells or a cell
containment member. In some embodiments, a woven or non-woven
textile or knit may be built intrinsically into the laminate to
provide enhanced mechanical support for handleability,
implantation, and removal of the cell encapsulation device.
In either arrangement depicted in FIGS. 13A and B or FIGS. 14A and
B, the containment tubes 1305 or containment channels 1405 may be
layered such that the containment tubes 1305 or containment
channels 1405 are parallel or substantially parallel to each other
along a length of the implantable apparatus. In some embodiments,
the containment tubes 1305 or containment channels 1405 are in a
same horizontal plane. In embodiments in which the containment
tubes 1305 or containment channels 1405 include a shaping element,
the containment tubes 1305 or containment channels 1405 are
non-planar (i.e., not planar, not lying in a single plane) or
provided in various planes. Alternative to the two dimensional
layering arrangements shown in FIGS. 13A and B or FIGS. 14A and B,
the containment tubes 1305 or containment channels 1405 may be
stacked in a three dimensional arrangement as shown in FIGS. 15 and
16, or staggered in a three dimensional arrangement, for example a
woven mesh configuration, as shown in FIG. 17A. The three
dimensional arrangements can be used to provide the containment
tubes 1305 or channels 1405 in a stacked or a staggered (in the x,
y, and/or z direction) orientation.
In a further embodiment depicted in FIG. 17B, the containment tubes
1705 (or channels (not depicted)) may have a substantially planar
arrangement with off-axis interconnection members 1730 to form a
lattice configuration. "Off-axis", as used herein, is meant to
describe interconnection members 1730 that are connected to the
containment tubes 1705 at an angle greater than zero degrees and
less than 90 degrees. In the cell encapsulation device depicted in
FIG. 17B, the interconnection members 1730 are oriented at an angle
about 45 degrees with respect to the containment tubes 1705 to form
the lattice configuration. The containment tubes 1705 are fluidly
connected to each other through the interconnection members 1730.
Thus, flow into one containment tube 1705 may pass through the
interconnection members 1730 into an adjacent containment tube(s)
1705. In such a "`lattice" embodiment, the containment tubes 1705
contains cells directly, and do not typically contain a therapeutic
device, although containing a therapeutic device is not prohibited.
Although not depicted, a manifold(s), a resealable port(s), or
resealable caps(s) may be positioned on the distal end 1712 or the
proximal end 1714.
In another embodiment, depicted generally in FIG. 17C, a cell
encapsulation device 1750 may include containment tubes
interconnected by interconnection members 1740 that have any
orientation, e.g., off-axis or perpendicular with respect to the
containment tubes 1705. As shown in FIG. 17C, the interconnection
members 1740 connect the containment tubes 1705 at various angles
as well as perpendicular to the containment tubes 1705, giving the
cell encapsulation device 1750 a more random configuration of
interconnection members 1740. The containment tubes 1705 are
fluidly connected to each other through the interconnection members
1740. Thus, flow into one containment tube 1705 may pass through
the interconnection members 1740 into an adjacent containment
tube(s) 1705. Also, the cell encapsulation device 1750 generally
contain cells, although the inclusion of one or more therapeutic
device in the containment tubes 1705 is not prohibited. Although
not depicted, a manifold(s), a resealable port(s), or resealable
caps(s) may be positioned on the distal end 1712 or the proximal
end 1714.
Looking at FIGS. 18A and 18B, a resealable port and/or a manifold
can have a variable compliance. In some embodiments, the resealable
port and/or the manifold may have a less compliant structure 1805
(shown in FIG. 18A) for an intended use of the encapsulation device
that requires a more rigid structure, e.g., implantation on the
surface of a metal plate or bone or within a metal plate or bone.
For example, the resealable port and/or the manifold may be a
singular integrated structure, as generally shown in FIG. 18A. In
other embodiments, the resealable port and/or the manifold may have
a more compliant structure 1810 (shown in FIG. 18B) for an intended
use of the encapsulation device that requires a more flexible
structure, e.g., implantation in a subcutaneous region or on a
surface of an organ or within an organ. For example, the resealable
port and/or the manifold may have hinge-like structures 1815
positioned between the various openings 1820. In some embodiments,
the hinge-like structures 1815 may be formed of a material such as
expanded PTFE or other flexible biocompatible material.
Alternatively, a shaping element, as discussed in detail herein,
which may include a shape memory material or structure made
therefrom, may be used in the construction of the resealable port
and/or the manifold to impart a more compliant structure.
In other embodiments, one or more cell containment member (or other
therapeutic device) may be housed within the containment tubes. In
some embodiments, a cell containment member can be designed to seal
with an interface of the resealable port and/or the manifold such
that the cell containment member is the sealing surface (i.e., the
cell containment member is self-sealing). Turing to FIG. 19, a
manifold 1910 is depicted with a cell containment member 1900
positioned partially in one of the openings 1905. The cell
containment member 1900 contains a sealing member 1920 such that
when the cell containment member 1900 is fully inserted into the
opening 1905, it is sealed to the opening 1905 of the manifold. The
cell containment member 1900 may also include a grasping structure
1915 (e.g., a tab) such that a clinician can hold the grasping
structure 1915 to hold or manipulate (e.g., insert or remove) the
cell containment member 1900. The cell containment member 1900 can
be repeatedly sealed and unsealed via sealing member 1920 to the
manifold 1910. It is to be appreciated that a similar or identical
containment member 1900 may be used to seal and reseal to a
resealable port. The sealing member 1920 may be attached to the
manifold or resealable port such as, for example, with friction, by
clamping, or with a screw comprised of threads and grooves.
V. Encapsulation Device with Central Manifold
FIG. 20A shows an encapsulation device containing a single
containment tube with a centrally located manifold in accordance
with various embodiments of the present disclosure. It is to be
appreciated that the term "centrally" as used herein is meant to
include a distance surrounding the center point such that the
manifold may not be perfectly centered. In other embodiments, the
manifold may be positioned a distance off-center or nearer to the
proximal or distal end. The encapsulation device 2000 may include a
containment tube 2005, a distal end 2010, a proximal end 2015, a
point 2020 between the distal end 2010 and the proximal end 2015
(e.g., center or off center by a predetermined distance), a divider
element 2035, and a manifold 2025 having a single connection port
2030. The divider element 2035 enables the flow of a fluid
containing cells (or other biologic moiety) to be divided such that
a portion of the cells flow in a distal direction and a portion of
the cells flow in a proximal direction. It is to be appreciated
that a cell containment member (or other therapeutic device) may be
placed inside the containment tube 2005 though the connection port
2030 in the manifold 2025.
FIG. 20B shows an encapsulation device containing two containment
tubes with a centrally located manifold in accordance with various
embodiments. The encapsulation device 2000 includes a first
containment tube 2040 and a second containment tube 2045, and a
manifold 2025 fluidly connecting the first and second containment
tubes 2040, 2045 (e.g., at first access ports of the first and
second containment tubes (not depicted)) and having a single
connection port 2030. The manifold is positioned at a point 2020
between the distal end 2015 of the first containment tube 2040 and
the distal end 2010 of the second containment tube 2045. It is to
be appreciated that a cell containment member (or other therapeutic
device) may be placed inside each of the containment tubes 2040,
2045 though the connection port 2030 in the manifold 2025.
FIG. 21 depicts a cell encapsulation device 2100 that includes a
plurality of containment tubes 2105 that have a distal end 2110 and
a proximal end 2115, a point 2120 between the first access ports
2145 at the distal end 2110 and the second access ports 2135 at the
proximal end 2115. The point 210 may be center or off center by a
predetermined distance. In addition, the manifold 2125 has multiple
connection ports 2130 that are fluidly connected to the first and
second access ports 2135, 2145. In some embodiments, the manifold
2125 is centrally located between the first and second access ports
2135, 2145. as is exemplified in FIG. 33. In other embodiments, the
manifold may be located off-center or more towards the proximal end
2115 or the distal and 2110, as is exemplified in FIG. 34. In some
embodiments, the manifold 2125 includes divider elements (not
shown) that enable the flow of a fluid containing cells (or other
biologic moiety) to be divided such that a portion of the cells
flow in a distal direction and a portion of the cells flow in a
proximal direction. It is to be noted that cell containment members
(or other therapeutic devices) may be placed inside the containment
tubes 2105 though the connection ports 2130. In addition, although
not depicted, the encapsulation device 2100 could be formed of a
plurality of first containment tubes and second containment tubes
such as is described with reference to FIG. 20B. In some
embodiments, resealable ports (not shown) may be fluidly connected
to the containment tubes at the proximal end 2115 and the distal
end 2110. In other embodiments, resealable caps (not depicted) may
be used to close off and seal the containment tubes 2105.
FIG. 22 depicts cell encapsulation members being inserted in an
encapsulation device 2200 that has been implanted under skin 2205
and subcutaneous tissue 2210, and into tissue bed 2260 in
accordance with some embodiments. The encapsulation device 2200 may
include a point 2230 between the distal end 2220 and the proximal
end 2225 (e.g., center or off center by a predetermined distance)
of the containment tube 2215, and a manifold 2235 having an
connection port 2240. In the embodiment depicted in FIG. 22, a
first cell encapsulation device 2250 is being inserted into the
containment tube 2215 proximally (towards the proximal end 2240 of
the containment tube 2215) and a second encapsulation device 2255
is being inserted into the containment tube 2015 distally (towards
the distal end 2245 of the containment tube 2015). It is to be
appreciated that an encapsulation device having two containment
tubes as depicted in FIG. 20B may be implanted as shown with
reference to FIG. 22 and a cell containment member may be inserted
into each containment tube. Advantageously, in the embodiments
shown in FIGS. 20A-22, the connection port of the manifold is close
to the skin while the containment tube(s) is at an appropriate
depth within the tissue bed, and, as a result, the shear force
required to remove the cells or cell containment member
(therapeutic device) is reduced.
As discussed with respect to the encapsulation devices shown in
FIGS. 11-19, the encapsulation devices depicted in FIGS. 20A-22 may
further include one or more resealable ports that provides an
access point through which cells or one or more cell containment
member (or other therapeutic device) may be moved in and out of the
luminal region of the containment tubes, one or more flush ports
that provide an access point through which a fluid stream can be
delivered to the luminal region of the containment tubes to flush
the luminal region of the containment tubes and/or one or more cell
containment member housed within the containment tubes. The cell
containment member can be designed to seal with an interface of the
resealable port, the manifold, and/or the access port.
VI. Bio-Absorbable Materials
FIGS. 23-30 depict various embodiments that include an amount of a
bio-absorbable material distributed on one or more components of an
implantable encapsulation device. The bio-absorbable material may
be formed as a solid (molded, extruded, or crystals), a
self-cohered web, a raised webbing, or a screen. In some
embodiments, one or more layers of a bio-absorbable material(s) are
attached to a non-bio-absorbable material having macroscopic
porosity to allow for cell permeation to form a composite. In other
embodiments, a non-bio-absorbable having microscopic porosity to
decrease or prevent cell permeation is releasably attached to a
porous self-cohered web to permit atraumatic removal of the
containment tube from the body of a patient days following
implantation. Resorbing into the body can promote favorable type 1
collagen deposition, neovascularization, and a reduction of
infection. In other examples, a bio-absorbable material may be
incorporated onto the cell encapsulation device as a powder.
Non-limiting examples of suitable bio-absorbable materials include,
but are not limited to, polyglycolide:trimethylene carbonate
(PGA:TMC), polyalphahydroxy acid such as polylactic acid,
polyglycolic acid poly (glycolide), and
poly(lactide-co-caprolactone), poly(caprolactone),
poly(carbonates), poly(dioxanone), poly (hydroxybutyrates),
poly(hydroxyvalerates), poly (hydroxybutyrates-co-valerates), and
copolymers and blends thereof.
FIG. 23 shows an encapsulation device 2300 that includes an amount
of a bio-absorbable material interspersed as a powder or bump like
structures 2305 on a surface of a containment tube 2310. FIG. 24
depicts an encapsulation device 2400 that includes an amount of a
bio-absorbable material(s) interspersed as a powder or bump like
structures 2405 on the surface of the containment tubes 2410. FIG.
25 shows an amount of a bio-absorbable material(s) I on a surface
of a film 2500 in a screen or raised webbing configuration 2505.
The bio-absorbable material(s) can be used to support the film 2500
to minimize, or even prevent, pillowing of the film 2500 once
captive cells begin to multiply and grow on the bio-absorbable
material and surface of the film 2500. In some embodiments, the
bio-absorbable material can be a temporary bio-absorbable material
such as a polymer or metal (e.g., magnesium). The film 2500 may be
used to form various components of a single containment tube and
multiple containment tube encapsulation devices.
FIG. 26 shows an encapsulation device 2600 that includes an amount
of a bio-absorbable material(s) interspersed as a bump-like
structures 2610 and a bio-absorbable material having a tapered
leading edge 2605 at an end of a containment tube 2620. FIG. 27
shows an encapsulation device 2700 that includes a bio-absorbable
material as a solid structure 2705 with a tapered leading edge at
an end of the containment tubes 2710. FIG. 28 depicts an
encapsulation device 2800 that includes a bio-absorbable material
2805 as a solid structure having a tapered leading edge at an end
of the channels 2810. The bio-absorbable material may also be
interspersed as a self-cohered web structure between the
containment channels 2810 to provide additional longitudinal
support to the containment channels. Incorporating bio-absorbable
components into an encapsulation device helps to facilitate ease of
implantation. For example, the bio-absorbable material may be
temperature sensitive. In particular, the bio-absorbable material
is much stiffer at colder temperatures and softens at higher
temperatures (e.g., body temperature once implanted) so that the
bio-absorbable material becomes more conformable and compliant
after implantation. As a result, the longitudinal strength, as well
as tapered leading edges formed of a bio-absorbable material may
allow a clinician to place the implantable apparatus in a patient
with less effort and trauma to the host, and upon implantation, the
bio-absorbable material becomes more conformable and compliant.
FIG. 29 shows an encapsulation device 2900 that includes a
combination of a bio-absorbable material 2905 in a solid, tapered
structure with a tapered leading edge as well as an amount of a
bio-absorbable material distributed over the surface of the
containment tube 2920 as bump like structures 2910. FIG. 30 depicts
an encapsulation device 3000 that includes a combination of a
bio-absorbable material 3005 in a solid, tapered structure with a
tapered leading edge and as a distribution of bump like structures
3010 on a surface of the containment tubes 3020.
VII. Facilitated Nutrient Transport
Certain materials are known to have high oxygen permeability, such
as, for example, perfluorocarbon emulsions, fluorohydrogels,
silicone oils, silicone hydrogels, soybean oils, silicone rubbers,
polyvinyl chloride, and combinations thereof. Such high oxygen
permeable materials can be utilized in the material construction of
the implantable apparatus, such as in one or more of the
containment tubes, caps, manifolds, access ports, grasping
structures, or therapeutic devices. In one embodiment, one or more
of the therapeutic devices and/or cell containment tubes includes a
highly oxygen permeable material. High oxygen permeable materials
may be utilized in the form of a coating onto one or more of the
porous polymeric membrane(s) or laminate forming the containment
tube, onto one or more of the seams or seals interposed between
each containment channel, or onto one or more of the containment
channels with a bump structure. Alternatively, high oxygen
permeable materials may be used in the form of a filling agent that
may be filled partially or filled completely into the void spaces
of the porous polymeric membrane or laminate forming, for example,
a containment tube. In some embodiments, high oxygen permeable
materials may be utilized in the form of a filling agent filled
partially or completely into the lumen of the containment tube.
EXAMPLES
Example 1
A first porous expanded polytetrafluoroethylene (ePTFE) film was
prepared according to the teachings of U.S. Pat. No. 3,953,566 to
Gore. The film had a mass per unit area of about 2.43 g/m2, a
thickness of about 8.9 .mu.m, a density of about 0.27 g/cc, a
longitudinal matrix tensile strength of about 663 MPa, a transverse
matrix tensile strength of about 14.3 MPa, and an IPA bubble of
about 4.83 kPA.
A second porous expanded polytetrafluoroethylene (ePTFE) film was
prepared according to the teachings of U.S. Pat. No. 5,476,589 to
Bacino. The film had a mass per unit area of about 1.46 g/m2, a
thickness of about 0.00012 inches [.about.3.05 .mu.m], a density of
about 0.48 g/cc, a longitudinal matrix tensile strength of about
101,321 psi (approximately 699 MPa), a transverse matrix tensile
strength of about 9288 psi (approximately 64.04 MPa), and an IPA
bubble of about 35.27 psi (approximately 243.2 kPa).
A third porous expanded polytetrafluoroethylene (ePTFE) film was
prepared according the teachings of U.S. Pat. No. 5,814,405 to
Branca. The film had a mass per unit area of 6.23 grams/m.sup.2, a
thickness of 0.0017 inches (approximately 43.2 .mu.m), an IPA
bubble point of 0.41 psi (approximately 2.83 kPA), a longitudinal
tensile strength of about 27974 psi (approximately 192.87 MPa), and
a transverse matrix tensile strength of about 5792 psi
(approximately 39.93 MPa).
A multi tube cell containing structure was manufactured by making a
continuous length of the first ePTFE into a tube with an inside
diameter of 0.089'' (approximately 2.26 mm) generally in accordance
with U.S. Pat. No. 6,617,151 to Newman, et al. (FIG. 9, steps 902
through 910 and corresponding text). The cell containment tubes
were formed with one (1) longitudinal wrap of the first ePTFE
membrane, six (6) overlapping helical wraps of the second ePTFE
membrane, and one (1) overlapping wrap of the third ePTFE membrane.
The cell containment tube was cut in to eight sections, each
section having a length of approximately 7''(approximately 17.8
cm). Into one end of each tube, a 0.089'' (approximately 2.26 mm)
mandrel was inserted.
A compression mold to form a resealable connection member was
fabricated in two halves (a top half and a bottom half), each half
having a smooth cornered rectangular cavity (approximately
1/4.times.0.164.times.1.7'' (approximately 6.4 mm.times.4.2
mm.times.43 mm) crossed by 8 cylindrical channels having a diameter
of 0.094'' (approximately 2.4 mm). The connection member was
constructed by forming one half of the connection member in the
mold by placing a sufficient quantity of a thermoplastic polymer
(THV500 from Dyneon America, Orangeburg, N.Y.) into the lower half
of the compression mold and heating to a temperature sufficient to
melt the thermoplastic polymer. Eight cylindrical mandrels were
then pressed into the melted polymer. The mold was then cooled and
the half piece was removed. This process was repeated to obtain the
second half of the connection member.
The halves of the connection member were placed into each half of
the compression mold and the 8 ePTFE tubes with the mandrels
inserted therein were laid across the mold with the end of the
ePTFE tubes located approximately halfway across the rectangular
cavity. The mold was closed and placed in a hot press (Wabash model
C30H-15-CPX manufactured by Wabash MPI, Wabash, Ind.). The press
was set to a temperature of 400.degree. F. (approximately
204.degree. C.), preheated for 5 minutes, and then closed at a
pressure of 0.3 tons (approximately 272 kg) for 2 minutes The mold
was removed from the hot press and cooled. This process was
repeated on the opposing end of the ePTFE tubes with the first
manifold not heated by the hot press.
Each tube could be filled with a cell displacing core and
therapeutic cells as described in U.S. Pat. No. 6,617,151 to
Newman, et al. or an appropriate length cell rod such as is
described in U.S. Pat. No. 5,787,900 to Butler, et al. The ends may
then be closed with a suitable cap.
Example 2
An EFEP thermoplastic film (NEOFLON.TM. RP-4020 available from
Daikin America, Orangeburg, N.Y.)) having a thickness of 1 mil
(approximately 0.025 mm) was cut by a laser programed to create 8
parallel rectangular openings 0.150''.times.5'' (approximately 3.81
mm.times.127 mm) with a space between openings of 0.1''
(approximately 2.5 mm) (7 places of film) with an excess of
thermoplastic film on each side and ends.
A multi-layer expanded PTFE (ePTFE) membrane was produced by
combining layers of different membranes bonded together with a
discontinuous fluoropolymer layer of fluorinated ethylene propylene
(FEP). The first layer (tight layer) consists of a membrane with a
smaller pore size and material properties listed in Table 3,
processed based on the teachings of U.S. Pat. No. 3,953,566 to
Gore. The second layer (open layer) consists of a larger pore size
membrane produced based on the teachings of U.S. Pat. No. 5,814,405
to Branca, et al., where a discontinuous layer of FEP has been
incorporated on the surface of this membrane based on the process
teachings of International Patent Application Publication WO
94/13469 to Bacino while allowing this substrate to still be air
permeable. The attributes of this open layer is listed in Table 1.
The first layer (tight layer) was then put in contact with the
second layer (open layer). The discontinuous FEP surface was
located between the two PTFE layers as they were heated above the
melting temperature of the FEP to create a bonded multilayer
composite membrane with the final properties identified in Table 1.
The ePTFE composite membrane was hydrophilically treated.
TABLE-US-00001 TABLE 1 Non- Bubble Point MD Force TD Force Contact
Pressure Airflow to Break to Break Mass/area Thickness (psi)
(L/hr@12 (lbf/in) (lbf/in) Layer (g/m.sup.2) (.mu.m) [.sup.~kPA]
mbar) [.sup.~N/M] [.sup.~N/M] First Layer 13.20 34.1 51.80 [357.1]
12.5 7.02 [1229] 11.58 [2028] Membrane Second layer 5 (1.3 34.1
1.70 [11.7] 3.87 [678] 0.48 [84.1] membrane with from FEP)
discontinuous FEP Final Multi- 17.90 73.4 52.10 [359.2] 13.3 8.07
[1413] 11.45 [2005] layer Membrane
A stack consisting of a stainless steel plate 8''.times.8''.times.
1/16'' thick (approximately 20.3 cm.times.20.3 cm.times.1.6 mm
thick), a silicone pad 6''.times.6'' 1/4'' thick (approximately
15.2 cm.times.15.2 cm.times.1.6 mm thick), and the hydrophilic
treated ePTFE membrane The ePTFE membrane was positioned with the
0.2 .mu.m side facing upwards (i.e., the 7.5 .mu.m was positioned
so that it faced downwards). The precut EFEP thermoplastic film was
laid on the ePTFE membrane. A second layer of an ePTFE membrane
identical to the first ePTFE membrane was placed on the EFEP
thermoplastic film with the 0.2 .mu.m side facing downwards. A
stainless steel sheet 6''.times.6''.times. 1/16'' thick
(approximately 15.2 cm.times.15.2 cm.times.1.6 mm thick) was placed
on top of the second ePTFE layer.
The stack was placed in a hot press (Wabash C30H-15-CPX from Wabash
MPI, Wabash Ind.) that was preheated to 437.degree. F.
(approximately 225.degree. C.) and closed to a set point pressure
of 0.2 tons (approximately 181 kg) for 5 minutes. The stack was
then removed from the hot press and cooled on a steel table with an
aluminum weight of approximately 2 kg on top of the stack until the
stack was cool to the touch.
After cooling, the thus-formed laminated sheet was removed and
trimmed to have an edge seam of approximately 0.1'' (approximately
0.25 cm). The ends were trimmed to be even with the end of the
openings. Thermoplastic ends (THV500 available from Dyneon America,
Orangeburg, N.Y.) molded as described in Example 1 were attached to
the ends.
Example 3
A simulated cell rod having a diameter of 0.084'' (approximately
0.21 cm) was formed as generally described in U.S. Pat. No.
6,617,151 to Newman et al. in the section entitled "Method of
Making Devices", column 11, line 18 to column 12, line 29. A multi
tube cell containing structure with the end sealed without loading
the device with cells was inserted into a connection member (as
described in Example 1). The manifold was affixed using a
fibrin/thrombin surgical glue.
A syringe filled with saline was connected to a 13 gauge blunt
needle. The blunt needle was compression fit into one opening in
the manifold connected to the cell containment tube into which the
simulated cell rod had been inserted. The plunger rod of the
syringe was then lightly tapped with a mallet to create a pressure
wave in the saline which served to push the simulated cell rod out
of the device.
Example 4
A first porous expanded polytetrafluoroethylene (ePTFE) film was
prepared according to the teachings of U.S. Pat. No. 3,953,566 to
Gore. The film had a mass per unit area of about 2.43 g/m2, a
thickness of about 8.9 .mu.m, a density of about 0.27 g/cc, a
longitudinal matrix tensile strength of about 663 MPa, a transverse
matrix tensile strength of about 14.3 MPa, and an IPA bubble of
about 4.83 kPA.
A second porous expanded polytetrafluoroethylene (ePTFE) film was
prepared according to the teachings of U.S. Pat. No. 5,476,589 to
Bacino. The film had a mass per unit area of about 1.46 g/m2, a
thickness of about 0.00012 inches [.about.3.05 .mu.m], a density of
about 0.48 g/cc, a longitudinal matrix tensile strength of about
101,321 psi (approximately 699 MPa), a transverse matrix tensile
strength of about 9288 psi (approximately 64.04 MPa), and an IPA
bubble of about 35.27 psi (approximately 243.2 kPa).
A third porous expanded polytetrafluoroethylene (ePTFE) film was
prepared according the teachings of U.S. Pat. No. 5,814,405 to
Branca. The film had a mass per unit area of 6.23 grams/m.sup.2, a
thickness of 0.0017 inches (approximately 43.2 .mu.m), an IPA
bubble point of 0.41 psi (approximately 2.83 kPA), a longitudinal
tensile strength of about 27974 psi (approximately 192.87 MPa), and
a transverse matrix tensile strength of about 5792 psi
(approximately 39.93 MPa).
A single tube cell containing structure was formed by making a
continuous length of the first ePTFE into a tube with an inside
diameter of 0.089'' (approximately 2.26 cm) generally in accordance
with teaching set forth in U.S. Pat. No. 6,617,151 to Newman, et
al. (FIG. 9, steps 902 through 910 and corresponding text). The
cell containment tube was formed with one (1) longitudinal wrap of
the first ePTFE membrane, six (6) overlapping helical wraps of the
second ePTFE membrane, and one (1) overlapping wrap of the third
ePTFE membrane. The cell containment tube was cut to obtain a
section approximately 6 cm in length.
Into one end (distal) of the shortened tube, a fluorinated ethylene
propylene (FEP) plug was inserted and sealed in place by use of
HOTweezers thermal wire strippers Model M10 with a handpiece 4C
modified with a 2.25 mm wire hole in the jaws (Meisei Corporation,
Westlake Village, Calif.) to melt the outer surface of the plug to
the interior of the ePTFE cell containment tube. Into the open end
of the cell containment tube a spline approximately 5 cm long
fabricated out of silicone with ribbed protrusions was inserted.
The spline was similar to that described in U.S. Pat. No.
5,980,889, to Butler et al. at FIG. 2, item 7.
A filling assembly was constructed by taking a Bionate 80A PCU
(polycarbonate polyurethane) (available from DSM Inc) tube with a
dimension of 0.89 mm inner diameter (ID) and 1.6 mm outer diameter
(OD) and approximately 5 cm long and attaching an adaptor to one
end. The adaptor was molded out of Bionate 80A PCU and had
dimension of 1.6 mm ID and 2.25 mm OD. The adaptor was cut to a
length of 3 mm. A mandrel was inserted into the PCU tube with
approximately 1 mm protruding from the end. The adaptor was then
placed over the Bionate 80A PCU tube so the ends of the Bionate 80A
PCU tube and adaptor were flush. The adaptor and Bionate 80A PCU
tube subassembly was inserted into the ePTFE cell containment tube
so that the mandrel just touched the internal spline. The adaptor,
Bionate 80A PCU tube, and ePTFE cell containment tube were sealed
together by the use of HOTweezers thermal wire strippers Model M10
with a handpiece 4C modified with a 2.25 mm wire hole in the jaws
(Meisei Corporation, Westlake Village, Calif.) with a cylindrical
opening measuring approximately 2.25 mm in diameter.
The entire assembly was leak checked by submersing in isopropyl
alcohol (IPA) and pressurizing the internals of the assembly plugs
with air to 5 psig (approximately 0.34 bar). No bubbles were
observed escaping from the device.
Example 5
A tube assembly was created by generally following the procedure
described in U.S. Pat. No. 5,565,166 to Witzko. The size of the
tube was 3 mm in diameter and the space between tubes was 1 mm. The
starting membrane had a mass per unit area of 42.4 grams/square
meter and a thickness of 0.07 mm. The tube assembly was trimmed so
as to be 8 tubes wide and 16.5 cm long.
A compression mold to form a resealable connection member was
fabricated in two halves (a top half and a bottom half), each half
having a smooth cornered rectangular cavity (approximately
1/4.times.0.164.times.1.7'' (approximately 6.4 mm.times.4.2
mm.times.43 mm) crossed by 8 cylindrical channels having a diameter
of 3 mm). The connection member was constructed by forming one half
of the connection member in the mold by placing a sufficient
quantity of a thermoplastic polymer (THV500 from Dyneon America,
Orangeburg, N.Y.) into the lower half of the compression mold and
heating to a temperature sufficient to melt the thermoplastic
polymer. Eight cylindrical mandrels were then pressed into the
melted polymer. The mold was then cooled and the half piece was
removed. This process was repeated to obtain the second half of the
connection member.
The half pieces were placed into each half of the mold and 8 ePTFE
tubes with 1.0 mm mandrels inserted into the end of each tube were
laid across the mold with the end of the ePTFE tube approximately
halfway across the rectangular cavity. The top half of the mold was
assembled and the mold placed in a hot press above the melt
temperature of the thermoplastic polymer. The mold was held in the
hot press for a sufficient time to melt the thermoplastic polymer
then fully closed. The mold was removed from the hot press and
cooled. This was repeated on the opposing end of the ePTFE tubes
with the first manifold not heated by the hot press.
The thermoplastic polymer used for this example was THV500 from
Dyneon (Dyneon America, Orangeburg, N.Y.) and the press was set to
a temperature of 400.degree. F. (approximately 204.degree. C.),
preheated for 5 minutes, and then closed at 0.3 tons (approximately
272.2 kg) for 2 minutes.
Each tube could be filled with a cell displacing core and
therapeutic cells as described in U.S. Pat. No. 6,617,151 to Newman
or an appropriate length cell rod as described in U.S. Pat. No.
5,787,900 to Butler, et al. The ends would then be closed with a
suitable cap. Each tube could also be filled with cells without a
cell displacing core. The diameter of each tube may be 0.5 mm or
less, 0.25 mm or less, or 0.13 mm or less.
Example 6
Three layers of an open (porous) microstructure ePTFE membrane as
taught in U.S. Pat. No. 5,814,405 to Branca, et al. was wrapped on
a 40 mm OD SST mandrel. The membrane has a discontinuous coating of
fluorinated ethylene propylene(FEP) thermoplastic on one surface
which was used as an adhesive in the construct. The discontinuous
FEP coating maintained porosity while also providing a method of
adhering the ePTFE layers together. The discontinuous FEP coating
was applied according to the methods taught in U.S. Pat. No.
6,159,565, to Campbell et al. The ePTFE layers were wrapped onto
the mandrel in a "cigarette roll" fashion with the FEP side away
from the mandrel to prevent the ePTFE membrane from adhering to the
mandrel.
Next, 2 layers of a tight microstructure ePTFE membrane as taught
in U.S. Pat. No. 5,476,589 to Bacino were wrapped onto the ePTFE
construct. This ePTFE membrane was also provided with a
discontinuous coating of FEP as described previously The FEP was
also positioned away from the mandrel.
The mandrel and ePTFE construct were then placed in a convection
air furnace (Grieve, Model NT-1000 available from The Grieve
Corporation, Round Lake, Ill.) at a temperature above the melt
temperature of the FEP (320.degree. C.). After a 10 minute dwell at
320.degree. C., the mandrel and ePTFE construct were removed and
allowed to air-cool to ambient temperature. Once cool, the
construct was slit longitudinally and removed from the mandrel.
The ePTFE construct at this point was a planar multi-layer laminate
of ePTFE with a very open microstructure with no FEP on one side
and a very tight microstructure ePTFE with discontinuous FEP on the
opposing side. Next, the construct was folded in half so that the
tight microstructure side was positioned against itself.
Using a template manufactured from aluminum sheet, localized heat
was applied through the use of a Weller soldering iron Model
PU-120T, available from McMaster Carr. The localized heat re-melted
the FEP, causing local adherence of the construct. The adhered
pattern resulted in a planar construct with 7 channels of
un-adhered material and a channel at one end that allowed all of
the channels to communicate.
The flat pattern of the template was designed to form flat channels
having a length that approximated the circumference of a 4 mm
diameter. After trimming excess material with scissors, a quantity
of 7, 4 mm outside diameter plastic tubings were placed into the
un-adhered channels. The construct was then placed in a rudimentary
aluminum mold, shown in FIG. 33.
The mold was clamped in the closed position and silicone, part
number NuSil MED-1137, available from NuSil Corporation, Cupertibo,
Calif., was forced into the mold using a 20 CC syringe. The mold
and indwelling construct were placed in an air convection oven
(Yamatomo, Mod& DKN600, available from Yamatomo Scientific,
Tokyo, Japan) at 60.degree. C. After a dwell time of approximately
12 hours, the mold and construct were allowed to air cool to
ambient temperature. Upon cooling, the mold was opened and the part
was removed. The silicone required slight trimming of the flash.
This process resulted in a construct measuring approximately 54
mm.times.85 mm of laminated ePTFE with an open (porous)
microstructure exterior layer which will promote vascular ingrowth,
7 channels running from a silicone manifold at one end to a
communication channel at the opposing end. A silicone bead around
the periphery added sufficient stiffness for handling purposes. The
interior surface of the channels was of a very tight microstructure
to contain cells yet allow transport of nutrients and other
biomolecules. This construct, as shown in FIG. 34, could be used to
house cell rods, or if sized appropriately, used to house cells
alone.
Example 7
Three layers of a very open (porous) microstructure ePTFE membrane
as taught in U.S. Pat. No. 5,814,405 to Branca, et al. was wrapped
on a 40 mm OD SST mandrel. The ePTFE membrane had a discontinuous
coating of fluorinated ethylene propylene (FEP) thermoplastic on
one surface which was used as an adhesive in forming the construct.
The discontinuous coating maintained porosity while also providing
a method of adhering the ePTFE layers together. The discontinuous
FEP coating was applied according to U.S. Pat. No. 6,159,565, to
Campbell et al. The ePTFE layers were wrapped onto the mandrel in a
"cigarette roll" fashion with the FEP side positioned away from the
mandrel to prevent the ePTFE membranes from adhering to the
mandrel.
Next, 2 layers of a tight microstructure membrane as taught in U.S.
Pat. No. 5,476,589 to Bacino were wrapped onto the ePTFE construct.
This ePTFE membrane was also provided with a discontinuous coating
of FEP as described previously. The FEP was also positioned away
from the mandrel.
The mandrel and ePTFE construct were then placed in a convection
air furnace (Grieve, Model NT-1000 available from The Grieve
Corporation, Round Lake, Ill.) at a temperature above the melt
temperature of the FEP (320.degree. C.). After a 10 minute dwell at
320.degree. C., the mandrel and ePTFE construct were removed and
allowed to air-cool to ambient temperature. Once cool, the
construct was slit longitudinally and removed from the mandrel.
The ePTFE construct at this point was a planar multi-layer laminate
of ePTFE with a very open microstructure with no FEP on one side
and a very tight microstructure ePTFE with discontinuous FEP on the
opposing side. Next, the construct was folded in half so that the
tight microstructure side was positioned against itself.
The layered construct was then placed on a vacuum plate and covered
with a piece of Zinc Selenide (available from Thor Labs, Newton,
N.J.) in a 25 Watt CO2 laser. As vacuum was applied, the Zinc
Selenide "laser window" applied pressure to the ePTFE laminate.
Zinc Selenide allowed the CO2 laser beam to pass without coupling
to its energy. The laser beam was reduced in power and defocused
purposely so that it created heat, but not cut the ePTFE/FEP
laminate. By altering the power and speed settings and altering the
focal point, the beam was used to create focal heating of the
ePTFE/FEP laminate, thereby melting and re-flowing the FEP layer
and causing adhesion. Heating of the chamber containing the
laminates allowed further reduction of the laser power since the
laser beam only needed to raise the local temperature enough to
flow the FEP (approximately 285.degree. C.). For instance, if the
chamber was operating at 250.degree. C., the laser only needs to
raise the local temperature at the point of adherence by 35.degree.
C. to facilitate adhesion.
The adhered pattern resulted in a planar construct similar to the
ribbon-tube example, with 7 channels of un-adhered material and a
channel at one end that allowed all channels to communicate. This
assembly could then be over-molded with silicone as in the previous
example if desired. Additionally, this "laser heating" method of
assembly can be especially advantageous since hard tooling is not
necessary and device pattern alterations can be made by
programming.
Example 8
Three layers of an open (porous) microstructure ePTFE membrane as
taught in U.S. Pat. No. 5,814,405 to Branca, et al. was wrapped on
a 40 mm OD SST mandrel. The membrane has a discontinuous coating of
fluorinated ethylene propylene(FEP) thermoplastic on one surface
which was used as an adhesive in the construct. The discontinuous
FEP coating maintained porosity while also providing a method of
adhering the ePTFE layers together. The discontinuous FEP coating
was applied according to the methods taught in U.S. Pat. No.
6,159,565, to Campbell et al. The ePTFE layers were wrapped onto
the mandrel in a "cigarette roll" fashion with the FEP side away
from the mandrel to prevent the ePTFE membrane from adhering to the
mandrel.
Next, 2 layers of a tight microstructure membrane as taught in U.S.
Pat. No. 5,476,589 to Bacino were wrapped onto the ePTFE construct.
This ePTFE membrane was also provided with a discontinuous coating
of FEP as described previously. The FEP was also positioned away
from the mandrel.
The mandrel and ePTFE construct were then placed in a convection
air furnace (Grieve, Model NT-1000 available from The Grieve
Corporation, Round Lake, Ill.) at a temperature above the melt
temperature of the FEP (320.degree. C.). After a 10 minute dwell at
320.degree. C., the mandrel and ePTFE construct were removed and
allowed to air-cool to ambient temperature. Once cool, the
construct was slit longitudinally and removed from the mandrel.
The ePTFE construct at this point is a planar multi-layer laminate
of ePTFE with a very open microstructure with no FEP on one side
and a very tight microstructure ePTFE with discontinuous FEP on the
opposing side. Next, the construct was folded in half so that the
tight microstructure side was positioned against itself.
Using a template manufactured from aluminum sheet and shown in FIG.
35, localized heat was applied through the use of a Weller
soldering iron Model PU-120T available from McMaster Carr. The
localized heat re-melted the FEP, causing local adherence of the
construct. The adhered pattern resulted in a planar construct with
7 channels of un-adhered material and a channel at one end that
allowed all channels to communicate. The flat pattern of the
template was designed to form flat channels having a length that
approximated the circumference of a 4 mm diameter. The excess
material was trimmed away and one of the channels was partially
separated and designated as the flush port.
The construct may then be over-molded and/or have manifolds
installed as in Example 6 as appropriate. This description will
yield a cell containment device with multiple channels and a flush
port which will facilitate removal of cell rods from within.
Example 9
Three layers of an open (porous) microstructure ePTFE membrane as
taught in U.S. Pat. No. 5,814,405 to Branca, et al. was wrapped on
a 40 mm OD SST mandrel. The membrane has a discontinuous coating of
fluorinated ethylene propylene(FEP) thermoplastic on one surface
which was used as an adhesive in the construct. The discontinuous
FEP coating maintained porosity while also providing a method of
adhering the ePTFE layers together. The discontinuous FEP coating
was applied according to the methods taught in U.S. Pat. No.
6,159,565, to Campbell et al. The ePTFE layers were wrapped onto
the mandrel in a "cigarette roll" fashion with the FEP side away
from the mandrel to prevent the ePTFE membrane from adhering to the
mandrel.
Next, 2 layers of a tight microstructure membrane as taught in U.S.
Pat. No. 5,476,589 to Bacino were wrapped onto the ePTFE construct.
This ePTFE membrane was also provided with a discontinuous coating
of FEP as described previously. The FEP was also positioned away
from the mandrel.
The mandrel and ePTFE construct were then placed in a convection
air furnace (Grieve, Model NT-1000 available from The Grieve
Corporation, Round Lake, Ill.) at a temperature above the melt
temperature of the FEP (320.degree. C.). After a 10 minute dwell at
320.degree. C., the mandrel and ePTFE construct were removed and
allowed to air-cool to ambient temperature. Once cool, the
construct was slit longitudinally and removed from the mandrel.
The ePTFE construct at this point is a planar multi-layer laminate,
of ePTFE with a very open microstructure with no FEP on one side
and a very tight microstructure ePTFE with discontinuous FEP on the
opposing side. Next, the construct was folded in half so that the
tight microstructure side was positioned against itself.
Using a template manufactured from aluminum sheet and shown in FIG.
35, localized heat was applied through the use of a Weller
soldering iron Model PU-120T available from McMaster Carr. The
localized heat re-melted the FEP, causing local adherence of the
construct. The adhered pattern resulted in a planar construct with
7 channels of un-adhered material and a channel at one end that
allowed all channels to communicate. The flat pattern of the
template was designed to form flat channels having a length that
approximated the circumference of a 4 mm diameter. After trimming
excess material with scissors, a quantity of 7, 4 mm outside
diameter plastic tubings were placed into the un-adhered channels.
The construct was then placed in a rudimentary aluminum mold shown
in FIG. 33.
The mold was clamped in the closed position and preheated to
approximately 200.degree. C.). After preheating, a molten blend of
polyglycolic acid and trimethylene carbonate (PGA:TMC) as taught in
U.S. Pat. No. 6,165,217 to Hayes, was injected into the mold. Once
the mold channels were full, the mold was quenched in room
temperature water to facilitate rapid cooling. Upon cooling, the
mold was separated and the part was removed. The resultant device
resembles that from Example 6 except that the molded stiffener bead
around the periphery was made of a bio-absorbable polymer. The bead
may be shaped in order to provide rigidity and even may be tapered
or pointed to facilitate insertion into a patient.
Although PGA:TMC is described, other bio-absorbable polymers may be
utilized. Choices may be affected by desired needs (such as
stiffness) and/or degradation profiles. Since many of
bio-absorbable polymers are melt processable, manufacturing
processes may include extrusion, injection molding and additive
manufacturing techniques (such as, for example, 3-D printing).
The biodegradable portion of this device may also include metals
(such as magnesium). In this case, the metals may be machined or
formed as separate components and adhered in the final assemble
through the use of adhesives (such as previously mentioned
FEP).
Example 10
Three layers of an open (porous) microstructure ePTFE membrane as
taught in U.S. Pat. No. 5,814,405 to Branca, et al. was wrapped on
a 40 mm OD SST mandrel. The membrane has a discontinuous coating of
fluorinated ethylene propylene(FEP) thermoplastic on one surface
which was used as an adhesive in the construct. The discontinuous
FEP coating maintained porosity while also providing a method of
adhering the ePTFE layers together. The discontinuous FEP coating
was applied according to the methods taught in U.S. Pat. No.
6,159,565, to Campbell et al. The ePTFE layers were wrapped onto
the mandrel in a "cigarette roll" fashion with the FEP side away
from the mandrel to prevent the ePTFE membrane from adhering to the
mandrel.
Next, 2 layers of a tight microstructure membrane as taught in U.S.
Pat. No. 5,476,589 to Bacino were wrapped onto the ePTFE construct.
This ePTFE membrane was also provided with a discontinuous coating
of FEP as described previously. The FEP was also positioned away
from the mandrel.
The mandrel and ePTFE construct were then placed in a convection
air furnace (Grieve, Model NT-1000 available from The Grieve
Corporation, Round Lake, Ill.) at a temperature above the melt
temperature of the FEP (320.degree. C.). After a 10 minute dwell at
320.degree. C., the mandrel and ePTFE construct were removed and
allowed to air-cool to ambient temperature. Once cool, the
construct was slit longitudinally and removed from the mandrel.
The ePTFE construct at this point is a planar multi-layer laminate,
of ePTFE with a very open microstructure with no FEP on one side
and a very tight microstructure ePTFE with discontinuous FEP on the
opposing side. Next, the construct was folded in half so that the
tight microstructure side was positioned against itself.
Using a template manufactured from aluminum sheet and shown in FIG.
35, localized heat was applied through the use of a Weller
soldering iron Model PU-120T available from McMaster Carr. The
localized heat re-melted the FEP, causing local adherence of the
construct. The adhered pattern resulted in a planar construct with
7 channels of un-adhered material and a channel at one end that
allowed all channels to communicate. The flat pattern of the
template was designed to form flat channels having a length that
approximated the circumference of a 4 mm diameter. After trimming
excess material with scissors, a quantity of 7, 4 mm outside
diameter silicone beads were inserted into the un-adhered
channels.
This procedure was repeated so as to acquire 2 identical ePTFE
constructs. Each ePTFE construct had a silicone bead filling each
channel. Next, each ePTFE construct was placed in an aluminum mold
that oriented the construct in a configuration in which the
majority of the construct is planar and the open ends of the
channels were bent at an approximately 90 degrees up, out of plane
orientation. The other construct placed in the mold was a mirror
image to the first. Each device was configured "back-to-back", with
all channel open-ends held in close proximity and in a bent up, out
of plane orientation.
The mold was clamped in the closed position and silicone, part
number NuSil MED-1137, available from NuSil Corporation, Cupertibo,
Calif., was forced into the mold using a 20 CC syringe. The mold
and indwelling construct were placed in an air convection oven
(Yamatomo, Model DKN600 available from Yamatomo Scientific, Tokyo,
Japan) at 60.degree. C. After a dwell time of approximately 12
hours, the mold and construct were allowed to air cool to ambient
temperature. Upon cooling, the mold was opened and the part was
removed from the mold. The silicone beading (qty=14) were removed
from the channels.
This process resulted in a construct measuring approximately 54
mm.times.120 mm of laminated ePTFE with an open (porous)
microstructure exterior layer which will promote vascular ingrowth
with 14 channels running from a silicone manifold at the center to
2 communication channels (one at each end). A silicone bead placed
around the periphery added sufficient stiffness for handling
purposes. The interior surface of the channels were of a tight
microstructure to contain cells yet avow transport of nutrients and
other biomolecules. This construct could be used to house cell
rods, or if sized appropriately, used to house cells alone.
This center manifold configuration allows the ports to be accessed
approximately perpendicular to the surface of the patient's skin,
thereby reducing trauma caused during replacement of cell rods.
Also, by inserting the cell rods from the center of the device, the
shear forces required to remove them will be reduce by
approximately one half.
The invention may also be described by the following:
1. An implantable encapsulation device comprising: a plurality of
containment tubes interconnected by connection members, each said
containment tube having a first access port at a first end thereof
and a second access port at a second end thereof, wherein said
containment tubes are substantially parallel to each other along a
length of said device.
2. The device of claim 1, wherein said connection members are
periodically spaced along a length of said containment tubes a
distance from each other; or further comprising resealable caps
affixed to said second access ports to seal said second end of said
containment tubes; or wherein said containment tubes comprise a
permeable membrane including an inner cell retentive layer and an
outer vascularizing layer; or wherein said containment tubes have
thereon a bio-absorbable material; or wherein said containment
tubes are stacked upon one another in a z-direction; or wherein
each of the plurality of containment tubes maintains a consistent
cylindrical cross-section; or wherein said containment tubes
comprise a shape memory material.
3. The device of claim 1, further comprising a removable manifold
fluidly connected to said containment tubes at said first end.
4. The device of claim 3, further comprising a flush port and a
tube fluidly connected to said removable manifold.
5. The device of claim 1, wherein said containment tube comprises a
lumen for the reception and containment of a biological moiety or
therapeutic device therein.
6. The device of claim 5, wherein the therapeutic device comprises
a drug delivery device, a gene therapy device, a cell encapsulation
device and combinations thereof.
7. The device of claim 6, wherein the one or more therapeutic
devices are removably sealed to a manifold fluidly connected to
said containment tubes at said first end.
8. The device of claim 7, wherein each of the one or more
therapeutic devices includes a grasping structure.
9. The device of claim 6, wherein said biological moiety is a
plurality of cells.
10. The device of claim 1, further comprising a bio-absorbable
material in at least one of a solid form and a self-cohered
web.
11. The device of claim 10, wherein the bio-absorbable material is
formed at the first end or the second end as the solid form with a
tapered leading edge.
12. A cell encapsulation device comprising: a plurality of
containment tubes, each said containment tube having a first access
port at a first end thereof and a second access port at a second
end thereof; at least one port sealably connected to said
containment tubes at said first end, said second end, or said first
and second ends; a manifold having one or more openings therein and
being fluidly connected to said containment tubes; and a flush port
fluidly connected to said manifold by a tube.
13. The device of claim 12, further comprising a sealable cap
affixed to said flush port; or wherein said manifold fluidly is
connected to said containment tubes at said first end or at said
second end; or wherein said manifold is located at a point located
between said end and said second end, and wherein said port is
sealably connected to said containment tubes at said first and
second ends; or wherein said manifold is centrally located between
said first end and said second end; or wherein said manifold
comprises hinged structures positioned between said openings; or
wherein each said containment tube is affixed to one said one of
more openings in said manifold; or wherein said flush port and said
tube lie in a same plane as said containment tubes; or wherein said
cell containment tubes comprise a permeable membrane including a
cell retentive layer and a vascularizing layer; or wherein each of
the plurality of containment tubes maintains a consistent
cylindrical cross-section; or wherein said containment tubes
comprise a shape memory material.
14. The device of claim 12, wherein said containment tube comprises
a lumen for the reception and containment of a biological moiety or
therapeutic device therein.
15. The device of claim 14, wherein the therapeutic device
comprises a drug delivery device, a gene therapy device, a cell
encapsulation device and combinations thereof.
16. The device of claim 14, wherein said biological moiety is a
plurality of cells.
17. The device of claim 15, wherein the therapeutic device is
removably sealed to a manifold fluidly connected to said
containment tubes at said first end.
18. The device of claim 17, wherein the therapeutic device includes
a grasping structure.
19. The device of claim 15, wherein said biological moiety is a
plurality of cells.
20. The device of claim 12, wherein said containment tubes have
thereon a bio-absorbable material.
21. The device of claim 20, wherein said bio-absorbable material is
in at least one of a solid form and a self-cohered web; or wherein
the bio-absorbable material is formed at the first end or the
second end of the apparatus as the solid form with a tapered
leading edge.
22. An implantable encapsulation device comprising: a laminate
sheet; and a plurality of containment channels formed by adhered
layers of the laminate sheet with seams interposed between each
containment channel, wherein the plurality of containment channels
are periodically connected to each other via the seams along a
length of the plurality of containment channels.
23. The device of claim 22, wherein the plurality of containment
channels are stacked upon one another in a z-direction; or further
comprising one or more therapeutic device housed within the
plurality of containment channels; or wherein the therapeutic
device comprises a drug delivery device, a gene therapy device, a
cell encapsulation device, and combinations thereof; or further
comprising at least one member selected from a manifold, an access
port, and a flush port.
24. An encapsulation device comprising: a plurality of containment
tubes substantially parallel to each other, each said containment
tube having a first access port at a first end thereof and a second
access port at a second end thereof; and a plurality of
interconnection members fluidly connecting adjacent containment
tubes.
25. The device of claim 24, wherein said interconnection members
are positioned at an angle relative to said containment tubes.
26. The device of claim 25, wherein said interconnection members
are positioned at an angle of zero degrees relative to said
containment tubes.
27. The device of claim 24, further comprising a biological moiety
housed within lumens of said containment tubes and interconnection
members.
The invention of this application has been described above both
generically and with regard to specific embodiments. It will be
apparent to those skilled in the art that various modifications and
variations can be made in the embodiments without departing from
the scope of the disclosure. Thus, it is intended that the
embodiments cover the modifications and variations of this
invention provided they come within the scope of the appended
claims and their equivalents.
* * * * *